Attempting to increase rate of Herceptin efficacy,decrease rate of Hercptn resistance
 

Since herceptin reportedly only works in 30% of 'appropriately targetted' her2 positive patients and as those in whom it does work in can become resistant with time, perhaps adding one of these two drugs to the regimen (even early on) could help it be more effective or stave off resistance:

1: Int J Cancer. 2006 Jan 19; [Epub ahead of print] Links

Increased PTEN expression due to transcriptional activation of PPARgamma by Lovastatin and Rosiglitazone.

Teresi RE, Shaiu CW, Chen CS, Chatterjee VK, Waite KA, Eng C.

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

Germline mutations in the tumor suppressor gene PTEN (protein phosphatase and tensin homolog located on chromosome ten) predispose to heritable breast cancer. The transcription factor PPARgamma has also been implicated as a tumor suppressor pertinent to a range of neoplasias, including breast cancer. A putative PPARgamma binding site in the PTEN promoter indicates that PPARgamma may regulate PTEN expression. We show here that the PPARgamma agonist Rosiglitazone, along with Lovastatin, induce PTEN in a dose- and time-dependent manner. Lovastatin- or Rosiglitazone-induced PTEN expression was accompanied by a decrease in phosphorylated-AKT and phosphorylated-MAPK and an increase in G1 arrest. We demonstrate that the mechanism of Lovastatin- and Rosiglitazone-associated PTEN expression was a result of an increase in PTEN mRNA, suggesting that this increase was transcriptionally-mediated. Compound-66, an inactive form of Rosiglitazone, which is incapable of activating PPARgamma, was unable to elicit the same response as Rosiglitazone, signifying that the Rosiglitazone response is PPARgamma-mediated. To support this, we show, using reporter assays including dominant-negative constructs of PPARgamma, that both Lovastatin and Rosiglitazone specifically mediate PPARgamma activation. Additionally, we demonstrated that cells lacking PTEN or PPARgamma were unable to induce PTEN mediated cellular events in the presence of Lovastatin or Rosiglitazone. These data are the first to demonstrate that Lovastatin can signal through PPARgamma and directly demonstrate that PPARgamma can upregulate PTEN at the transcriptional level. Since PTEN is constitutively active, our data indicates it may be worthwhile to examine Rosiglitazone and Lovastatin stimulation as mechanisms to increase PTEN expression for therapeutic and preventative strategies including cancer, diabetes mellitus and cardiovascular disease. (c) 2006 Wiley-Liss, Inc.

PMID: 16425225 [PubMed - as supplied by publisher]

"long version" of my "wondering out loud"--comments from RobinP, Gina, Al, anyone?
 

I frequently read articles stating that herceptin reportedly only works in 30%-35% of appropriately targeted her2 positive patients and that the majority of the patients it does work in can become resistant with time. Perhaps the former is because they were not testing her2 properly as recent articles have reported as high as 72% complete pathologic response when combining docetaxel and Herceptin as neoadjuvant therapy in Stage II and III patients.

In any case, since activation and increased expression of PTEN supposedly has much to do with herceptin efficacy, perhaps adding one of the following two drugs to the regimen (even early on) could help it be more effective or stave off resistance--lovastatin is an anticholesterol drug, rosiglitazone is an antidiabetes(type2)drug. Since IGFR1 signalling cross-talk is also felt to be a factor in herceptin resistance, perhaps Robin P’s admonition to keep exercising is all the more pertinent! Articles about the role of Vitamin D, omega 3s, orlistat, etc usually just state they are more than additive in their effect when combines with herceptin on breast cancer CELL LINES in vitro--found any articles which would imply that they would make herceptin more likely to be effective in an individual or decrease the likelihood of the development of resistance? Any and all thoughts appreciated!

1: Int J Cancer. 2006 Jan 19; [Epub ahead of print] Links

Increased PTEN expression due to transcriptional activation of PPARgamma by Lovastatin and Rosiglitazone.

Teresi RE, Shaiu CW, Chen CS, Chatterjee VK, Waite KA, Eng C.

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

Germline mutations in the tumor suppressor gene PTEN (protein phosphatase and tensin homolog located on chromosome ten) predispose to heritable breast cancer. The transcription factor PPARgamma has also been implicated as a tumor suppressor pertinent to a range of neoplasias, including breast cancer. A putative PPARgamma binding site in the PTEN promoter indicates that PPARgamma may regulate PTEN expression. We show here that the PPARgamma agonist Rosiglitazone, along with Lovastatin, induce PTEN in a dose- and time-dependent manner. Lovastatin- or Rosiglitazone-induced PTEN expression was accompanied by a decrease in phosphorylated-AKT and phosphorylated-MAPK and an increase in G1 arrest. We demonstrate that the mechanism of Lovastatin- and Rosiglitazone-associated PTEN expression was a result of an increase in PTEN mRNA, suggesting that this increase was transcriptionally-mediated. Compound-66, an inactive form of Rosiglitazone, which is incapable of activating PPARgamma, was unable to elicit the same response as Rosiglitazone, signifying that the Rosiglitazone response is PPARgamma-mediated. To support this, we show, using reporter assays including dominant-negative constructs of PPARgamma, that both Lovastatin and Rosiglitazone specifically mediate PPARgamma activation. Additionally, we demonstrated that cells lacking PTEN or PPARgamma were unable to induce PTEN mediated cellular events in the presence of Lovastatin or Rosiglitazone. These data are the first to demonstrate that Lovastatin can signal through PPARgamma and directly demonstrate that PPARgamma can upregulate PTEN at the transcriptional level. Since PTEN is constitutively active, our data indicates it may be worthwhile to examine Rosiglitazone and Lovastatin stimulation as mechanisms to increase PTEN expression for therapeutic and preventative strategies including cancer, diabetes mellitus and cardiovascular disease. (c) 2006 Wiley-Liss, Inc.

PMID: 16425225 [PubMed - as supplied by publisher]

*-35%
1: Br J Cancer. 2006 Jan 10; [Epub ahead of print]
Related Articles, Links
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PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer.

Fujita T, Doihara H, Kawasaki K, Takabatake D, Takahashi H, Washio K, Tsukuda K, Ogasawara Y, Shimizu N.

1Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, 700-8558 Okayama, Japan.

Trastuzumab is the only HER2/neu-directed therapy to have received Food and Drug Administration approval for the treatment of patients with metastatic breast cancer. The efficacy of trastuzumab depends on the HER2/neu status of the tumour and the patient's prior treatment, but even when patients are selected on the basis of HER2/neu gene amplification, the single-agent response rate ranges from 12 to 30% and few patients respond to trastuzumab monotherapy. Here, we propose PTEN as a predictive biomarker for trastuzumab efficacy. Human breast cancer SKBR3 and drug-resistant SKBR3/R cells were investigated. We also examined clinical samples from patients who had been treated with trastuzumab and analysed the relationship between trastuzumab efficacy and PTEN level. The PI3K/Akt signalling pathway was observed to be highly active in the drug-resistant cells, and their level of PTEN was low. Delivery of antisense PTEN duplex siRNA significantly decreased the trastuzumab chemosensitivity of parental SKBR3 cells, and marked activation of Akt signalling pathway was also recognised. Moreover, immunohistochemical investigation revealed that trastuzumab treatment was remarkably successful in cells with elevated PTEN expression. Along with the immune-system-associated cytotoxic mechanism, several mechanisms have been proposed for the effect of trastuzumab. 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.British Journal of Cancer advance online publication, 10 January 2006; doi:10.1038/sj.bjc.6602926 www.bjcancer.com.

PMID: 16404430 [PubMed - as supplied by publisher]

: Mol Cancer Ther. 2002 Jul;1(9):707-17.
Related Articles, Links
*
Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells.

Clark AS, West K, Streicher S, Dennis PA.

Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20889, USA.

To evaluate the role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in breast cancer cell survival and therapeutic resistance, we analyzed a panel of six breast cancer cell lines that varied in erbB2 and estrogen receptor status. Akt activity was constitutive in four cell lines and was associated with either PTEN mutations or erbB2 overexpression. Akt promoted breast cancer cell survival because a PI3K inhibitor, LY294002, or transient transfection of a dominant-negative Akt mutant inhibited Akt activity and increased apoptosis. When combined with therapies commonly used in breast cancer treatment, LY294002 potentiated apoptosis caused by doxorubicin, trastuzumab, paclitaxel, or etoposide. Potentiation of apoptosis by LY294002 correlated with induction of Akt by doxorubicin or trastuzumab alone that occurred before the onset of apoptosis. Similar results were observed with tamoxifen. Combining LY294002 with tamoxifen in estrogen receptor-positive cells greatly potentiated apoptosis, which was correlated with tamoxifen-induced Akt phosphorylation that preceded apoptosis. To confirm that the effects of LY294002 on chemotherapy-induced apoptosis were attributable to inhibition of Akt, we transiently transfected breast cancer cells with dominant-negative Akt and observed increased doxorubicin-induced apoptosis. Conversely, stably transfecting cells with constitutively active Akt increased Akt activity and attenuated doxorubicin-induced apoptosis. These studies show that endogenous Akt activity promotes breast cancer cell survival and therapeutic resistance, and that induction of Akt by chemotherapy, trastuzumab, or tamoxifen might be an early compensatory mechanism that could be exploited to increase the efficacy of these therapies.

PMID: 12479367 [PubMed - indexed for MEDLINE]



1: Int J Cancer. 2005 Sep 1;116(3):359-67.
Related Articles, Links
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Herceptin-induced inhibition of ErbB2 signaling involves reduced phosphorylation of Akt but not endocytic down-regulation of ErbB2.

Longva KE, Pedersen NM, Haslekas C, Stang E, Madshus IH.

Institute of Pathology, The University of Oslo, Rikshospitalet, Oslo, Norway.

The anti-proliferative effect of the ErbB2 specific antibody Herceptin in cells overexpressing ErbB2 has previously been explained by endocytic downregulation of ErbB2. However, in the following, we demonstrate that Herceptin inhibited proliferation of ErbB2 overexpressing cells without downregulating ErbB2. Herceptin did also not induce endocytosis of ErbB2. Herceptin was found to blunt proliferation of SKBr3 cells overexpressing EGFR, ErbB2, and ErbB3 and expressing functional PTEN, probably by recruiting PTEN to the plasma membrane. Akt was found to be constitutively phosphorylated both in SKBr3 cells overexpressing EGFR, ErbB2 and ErbB3, and in SKOv3 cells, overexpressing EGFR and ErbB2. However, phosphorylation of Akt was inhibited by Herceptin only in SKBr3 cells. SKOv3 cells, which lack the tumour suppressor protein Ras homolog member I, was found to have constitutively phosphorylated mitogen activated protein kinase and functionally increased Ras activity. SKOv3 cells further had low expression levels of PTEN. We thus confirm that the anti-proliferative effect of Herceptin in SKBr3 cells is due to recruitment of PTEN to the plasma membrane and conclude that Herceptin does not blunt phosphatidyl inositol 3 kinase-induced growth in cells with constitutive Ras activity. We further conclude that endocytic downregulation of ErbB2 does not contribute to Herceptin's antiproliferative effect.

PMID: 15800944 [PubMed - indexed for MEDLINE]

1: Cancer Cell. 2004 Aug;6(2):117-27.
Related Articles, Links
*
Comment in:
• Cancer Cell. 2004 Aug;6(2):103-4.

PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients.

Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D.

Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

The ErbB2-targeting antibody, trastuzumab (Herceptin), has remarkable therapeutic efficacy in certain patients with ErbB2-overexpressing tumors. The overall trastuzumab response rate, however, is limited and what determines trastuzumab response is poorly understood. Here we report that PTEN activation contributes to trastuzumab's antitumor activity. Trastuzumab treatment quickly increased PTEN membrane localization and phosphatase activity by reducing PTEN tyrosine phosphorylation via Src inhibition. Reducing PTEN in breast cancer cells by antisense oligonucleotides conferred trastuzumab resistance in vitro and in vivo. Patients with PTEN-deficient breast cancers had significantly poorer responses to trastuzumab-based therapy than those with normal PTEN. Thus, PTEN deficiency is a powerful predictor for trastuzumab resistance. Additionally, PI3K inhibitors rescued PTEN loss-induced trastuzumab resistance, suggesting that PI3K-targeting therapies could overcome this resistance.

PMID: 15324695 [PubMed - indexed for MEDLINE]

: Mol Cancer Ther. 2002 Jul;1(9):707-17.
Related Articles, Links
*
Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells.

Clark AS, West K, Streicher S, Dennis PA.

Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20889, USA.

To evaluate the role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in breast cancer cell survival and therapeutic resistance, we analyzed a panel of six breast cancer cell lines that varied in erbB2 and estrogen receptor status. Akt activity was constitutive in four cell lines and was associated with either PTEN mutations or erbB2 overexpression. Akt promoted breast cancer cell survival because a PI3K inhibitor, LY294002, or transient transfection of a dominant-negative Akt mutant inhibited Akt activity and increased apoptosis. When combined with therapies commonly used in breast cancer treatment, LY294002 potentiated apoptosis caused by doxorubicin, trastuzumab, paclitaxel, or etoposide. Potentiation of apoptosis by LY294002 correlated with induction of Akt by doxorubicin or trastuzumab alone that occurred before the onset of apoptosis. Similar results were observed with tamoxifen. Combining LY294002 with tamoxifen in estrogen receptor-positive cells greatly potentiated apoptosis, which was correlated with tamoxifen-induced Akt phosphorylation that preceded apoptosis. To confirm that the effects of LY294002 on chemotherapy-induced apoptosis were attributable to inhibition of Akt, we transiently transfected breast cancer cells with dominant-negative Akt and observed increased doxorubicin-induced apoptosis. Conversely, stably transfecting cells with constitutively active Akt increased Akt activity and attenuated doxorubicin-induced apoptosis. These studies show that endogenous Akt activity promotes breast cancer cell survival and therapeutic resistance, and that induction of Akt by chemotherapy, trastuzumab, or tamoxifen might be an early compensatory mechanism that could be exploited to increase the efficacy of these therapies.

PMID: 12479367 [PubMed - indexed for MEDLINE]

: Cancer Res. 2005 Dec 1;65(23):11118-28. Related Articles, Links

Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells.

Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ.

Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.

The majority of breast cancer patients who achieve an initial therapeutic response to the human epidermal growth factor receptor 2 (HER-2)-targeted antibody trastuzumab will show disease progression within 1 year. We previously reported the characterization of SKBR3-derived trastuzumab-resistant pools. In the current study, we show that HER-2 interacts with insulin-like growth factor-I receptor (IGF-IR) uniquely in these resistant cells and not in the parental trastuzumab-sensitive cells. The occurrence of cross talk between IGF-IR and HER-2 exclusively in resistant cells is evidenced by the IGF-I stimulation resulting in increased phosphorylation of HER-2 in resistant cells, but not in parental cells, and by the inhibition of IGF-IR tyrosine kinase activity leading to decreased HER-2 phosphorylation only in resistant cells. In addition, inhibition of IGF-IR tyrosine kinase activity by I-OMe-AG538 increased sensitivity of resistant cells to trastuzumab. HER-2/IGF-IR interaction was disrupted on exposure of resistant cells to the anti-IGF-IR antibody alpha-IR3 and, to a lesser extent, when exposed to the anti-HER-2 antibody pertuzumab. Heterodimer disruption by alpha-IR3 dramatically restored sensitivity to trastuzumab and resistant cells showed a slightly increased sensitivity to pertuzumab versus parental cells. Neither alpha-IR3 nor pertuzumab decreased HER-2 phosphorylation, suggesting that additional sources of phosphorylation other than IGF-IR exist when HER-2 and IGF-IR are not physically bound. Our data support a unique interaction between HER-2 and IGF-IR in trastuzumab-resistant cells such that cross talk occurs between IGF-IR and HER-2. These data suggest that the IGF-IR/HER-2 heterodimer contributes to trastuzumab resistance and justify the need for further studies examining this complex as a potential therapeutic target in breast cancers that have progressed while on trastuzumab.

PMID: 16322262 [PubMed - in process]

It is not my intention to alarm anyone...that's why I use the word reportedly
 

They also said her2+er+ tumors only made up 10% of her2+tumors for years and years until this year when the centralized/better testing required for the Herceptin trials in No. America and HERA trials came back with a figure more like 45%. And remember, herceptin research was almost given up because it was hardly more effective than control (because the patients they tried it on where not appropriately selected and/or inadequate/erroneous her2 testing had been carried out). As the mechanism(s) of action of herceptin are better understood, and her2testing improves and/or more reproducible/central testing is carried out, these statistics should probably improve. It is only with continued use of herceptin that we will see if/how often herceptin resistance occurs, whether it can be reversed by available/or soon to be available agents (lapatinib)and who it occurs in. Many on this site it seems have been on Herceptin for 6-8 years without loss of efficacy.

That said, any reports of ways which might relatively easily (and with few side effects) improve the chances of Herceptin function--flaxseed oil, primrose oil, even perhaps Xenical--are certainly welcome!

Sorry to have been so verbose this morning. I held this post for three days
while deciding whether its positive implications outweighed any negative thoughts it might entertain.

Hope this helps!
Lani

2nd year of adjuvant Herceptin
 

I really want to persue the 2nd year of adjuvant Herceptin as my first year is coming to an end in Feb 06. But I am hesitating so much in fear of developing resistance to it as mentioned in the above article. Anybody has any thoughts?

Julie

Herceptin "resistance" may not be the best term--it's still working, just needs help!
 

In the metastatic setting, they have found if tumors recur/progress on Herceptin it is usually best to keep the patient on herceptin and add something to it. So herceptin "resistance" may be a bad term. It still works, it is just the cancer may have found other ways to multiply that need to be blocked as well. It is like a puppy in the house--you may have blocked the front door, but it will eventually explore and found other doors to get out into the yard and chase that squirrel! It doesn't mean you should leave the front door open, only that you need to close more doors.

Hope this helps!
Lani

HER2 resistance
 

Hey Lani,

I think you are on the right track. I have to apologize and admit that I only skimmed the abstracts as I'm very tight on time these days due to Linda's tx.

Most of the stuff in the articles talks about the down-regulation of HER2.
Let me postulate 4 scenarios:

1. Let's assume herceptin is working but not optimally; I agree that you can downregulate HER2 say with oleic acids therefore weakening the HER2 receptors thus increasing suseptability to herceptin

2. The HER2/AKT/PI3K.....by down-regulating PI3K and upregulating PTEN which sensitizes the HER2 tumor cells to apoptosis.

3. Transciption: the dimerization of HER2 and EGFR (HER1) of HER3. In this case adding lapatinib or pertuzumab would be effective preventing transcription.

4. herceptin resistance: like any drug, herceptin will cause cells to develop resistance or habituate to the drug. It has been shown that herceptin resistant HER2 tumor cells can be re-sensitized to herceptin by adding an EGFR inhibitor such as lapatinib, iressa, centuximan or tarceva.

Here's my take: do molecular profiling on the tumor cells and target the therapy accordingly, (this doesn't sound like rocket science), ie. test for HER1 - 3, VEGF, PI3K, PTEN, ER, or........lets do a trial on active mets with herceptin + pertuzumab + avastin + lucentis (which attacks VEGF in a different way) + LY294002 + say a friendly chemo drug like Xeloda. If I personally, had stage 4 cancer; I would volunteer as what's the worst that will happen, I'll die young?? After that, maintainence with herceptin + lapatinib + Avastin (+ faslodex if ER+).

Diclaimer: don't believe me because I'm only a care-giver.

Al

Thanks Al for stating everything I would have said and more. What I find interesting is that there are a number of people on this site that are not herceptin resistent after years of therapy which I must say is quite encouraging. Wouldn't you just love to know what markers were in their bc tumors, ig. pTEN+?, Her1+,3+? etc.

RobinP

My guess is that it is only HER2 that is overexpressed and not HER1 or 3; therefore no transcription. It must be low in VEGF and PI3K as well....just thinking, Al

to continue or not
 

Apologies in advance for the scattergun approach of this post;

I started Herceptin with Taxol in March 2004. Taxol finished in July 2004, Herceptin paused for two months while I had radiotherapy.
Was put on three-weekly Herceptin regime after that and have managed to persuade them to keep me on since. I am tolerating it well apart from the aches and pains mentioned in another thread.

Decision time will be here again in March.

My instinct is to continue, if I can persuade them, as I am the equivalent of Stage III Grade III with all the nodes including post sternum implicated.

(Am NED at the moment)

At least continue until there is more evidence from the trials as to what the optimum length of time is to stay on Herceptin.

Anyone any thoughts on this?

stage 3?
 

Dear Cara,
It doesn't make sense to me that you should remain on herceptin indefinitely if you are stage 3. Does that mean that anyone with HER2 +++ BC (stage 1 incl.)should be on herceptin forever? My question being: where do you draw the line. We have stage 4 multiple mets fighting for herceptin and not getting it.
Sorry if that's not what you wanted to hear but........ unless a more compelling argument happens to surface, I'm not sure what you can do. I'm sure there are many here who will disagree with me but....... why would you want to go through this extra hassle of infusions etc if there doesn't appear to be a therapeutic advantage? However, I'm sure there are studies in the works to answer just that question.

Good luck,
Al

wow - I need to read this more carefully to try to understand what you all are saying. i guess my initial quesiton, though, to al, would be whether one can get lapatinib. i'm in the clinical trial of xeloda, with or w/out lapatinib, and i'm in the arm without it. if i end my participation in the trial, can i get it as a course of treatment?

For those who are on Herceptin now who are not stage 4, I agree with Al that Herceptin has got to stop at some point. I would assume that would be one to two years of therapy. Certainly, even with less therapy than that may be appropriate as the FinHer trail, of 9 weeks of Herceptin, was just as effective as one year of Herceptin. I really think what we'll see is a trend toward shorter Herceptin therapy; particularly to avoid cardiac side effects as the 9 weeks of Herceptin had zero cardiac risk.

I don't think prolonged Herceptin therapy prevents Herceptin resistance. As others here have mentioned, if you possess certain markers, you may become Herceptin resistant. I think we have an idea of what some of those markers may be pre-clinically, pTEN deficiency, perhaps high IGF and perhaps high Her3. However, researchers need to define if pre-clinical markers translate into the human experience. Hopefully, we will have a lot of answers to the significance of markers like pTEN from the HERA trail, should the investigators re-examine the tissue blocks from the trail participants. . Once this is determined then perhaps drugs like Lapatinib, IGF inhibitors, her3 inhibitors will be used in the mix with Herceptin in the adjuvant setting. However, many of these drugs are only available to the mets population now, and only in clinical trails.


I look forward to what the HERA trail investigators will find in the bc tissue blocks. I bet a lot of the Herceptin responders were positive not only for her2 but for her1 and 3 too. Anyway, what is her2 without its partners in crime; its not like her2 does its jaded act in solo.

Thanks, LANI, there is A LOT of good info here...
 

Lani, LUCKY YOU..you caught me AT HOME after my Herceptin yesterday...a RARE day off...so I will have a moment to send you an infamous GINA LONG ANSWER...but first a couple of short ones...

One reason that Herceptin alone has worked for me so long is probably because I do not have a PTEN problem...and I extremely over-express her-2. I have no pathology report to prove the PTEN one way or the other, but if I am reading the one article right...the PTEN problem that sometimes may block the efficacy of Herceptin is also often associated with hereditary bc...as far as we have been able to determine, there is no hereditary BC in my family. Both Grandmothers lived into their 90's, very healthy their whole lives, very robust hard-working women. Neither my mother nor my two sisters have any BC or other cancers and are relatively healthy. My mother, as I mentioned on an earlier post, will be 70 this year and looks as though she will probably live at least as long as her mom,--91 or actually even make it to the magic 100. The men in my family, due to their dangerous occupations in the coal mines and railroad, died accidental or emphysema- related deaths, but no cancer as far as we know, but my one paternal grandfather who did make it into his eighties had a bone scan suspicious for bone mets at the very end, but died of black-lung related causes before we could confirm cancer dx one way or the other.

The second thing about my longevity with Herceptin that you have to remember is that even though I have used it off and on since 1999...you have to keep in mind...that I did not take very MUCH of it...

This was my choice and of course, at the time, counter to all HERCEPTIN wisdom...In 1999, I think I took 4mg one week, then 2mg, then 2mg, etc for about 5 or 6 weeks and stopped for nearly a year...then in 2000, mets in liver returned..so I took another 6 or so hits of herceptin...regressed the lesions back out and then went another year off Herceptin before mets struck a third time...This time, I decided to test 11 or 12 hits of herceptin to see if MORE herceptin would buy me more time to progression, but --as if on its own circadian rhythm..the mets would return on cue by the following year...this went on for 4 years until my really good onc left town and I was put with another onc who at a certain point...refused to let me go OFF the herceptin...but even then, I pushed the envelope...first moving immediately to the every 3 weeks and then, against ALL advice...pushing that envelope and moving the the 6mg /per kg for the every 3 weeks out to 6mg one time every 6 weeks...I did this for over a year and a half, until last September, as though on cue, my mets acted up and I went back to the more normal dosing of 6mg/kg...so you see...over all, I have taken SO LITTLE herceptin, that even though I am nearly 7 years with mets out, I may have actually taken LESS DOSINGS of herceptin than the average gal, say only 3 years out who has followed the standard dosing recommendations, either weekly or bi-weekly or every 3 weeks.

The third BIG difference in my case is that for the whole 7 years, by accident, I have been getting daily amounts of more oleic acid than the normal person because every day, since around July 1999, I have taken more or less the following supplements: 500mg of evening primrose oil (oleic acid and GLA rich (I take NO MORE THAN 500mg daily and only because I was and am still PRE-menopausal...this supplement may not be good for some one post menopausal and is also contraindicated for anyone who is taking cumidun for their port or to keep their blood from clotting as evening primrose is a powerful anticoagulant in its own right...but also remember...I DON't have a port and have not had one since it was removed after initial chemo in 1998); 25,000 I.U. Vitamin A with 800 to 1,000 I.U. Vitamin D in Solgar's fish oil tab with safflower...which accidentally turned out to be a specially genetically engineered safflower oil filler, rich in guess what??? OLEIC ACID!!!; a good basic multi-vitamin that contains another 5,000 I.U. of A as in palmatic acid (not just beta-carotene) and another 400 IU of D with equal calc to mag ratios...like 100mg to 100mg--as I do NOT especially believe that her-2 folks, for any reason, should ingest supplemental calcium..long story --my multi also contains zinc but no iron and traces of micro-nutrients like boron, copper (to balance zinc), etc. not too much B-6--as it blocks oleic acid..fyi); I take about one fourth of a kelp tab as more than that makes me eat like a fiend..smile.., and MOST importantly, I take a lot of magnesium..as I am always low...300mg of country life with silica and horsetail for breakfast with either another 400mg of PURE mag or PURE mag orotate, followed by another 700 to even 1,000mg later in the day...depending on how my platelets look...; then, around the year 2000, I added 500mg to 1,000mg of olive leaf capsules to my regimen, again, unaware of the connection the Dr. Mendenez was to make in early January 2005, and off and on, I would test so many things...like Hulda Clarks' formula...really appreciated the cloves...and tend to have taken them instead of the tumeric to kill "progeny" but at the moment, as so many have recommended tumeric on this site and especially when I saw one 'patient' with bc mets basically every where Except NOT in THE LIVER--which was a bit bizarre and later learned that she was a daily taker of tumeric...I decided for protecting the liver, it must be useful...will let you know how it goes with me...although I really think ground cloves hits this same mechanism. I also took Dr. Clark's green walnut tincture off and on which may be rich in oleic acid as walnuts certainly are, and tested her wormwood, but it gave me so much neurapathy and made me feel so tired like I was back on taxotere that I could not keep taking it, and WELL, THERE are so many alternatives I have tested--no joke, I have saved every bottle for posterity..smile as I was sure no one would believe me if I did live for a while, but the main ones that worked for my her-2, other than what I wrote above that have helped me have been echinacea, artichoke (for liver, I am allergic to ragweed and have difficulty taking milk thistle as they run in same family), zinc oxide on the feet (as in Desitin--to keep my lymphs up and grans down), and certain macrolide classes and quinolone classes of antibiotics--but only those that disrupt PLASMID protein synthesis and that are designed to hit aerobic (air BREATHING) gram NEGATIVE bacteria...antibiotics designed to take out anaerobic or gram positive bacteria, such as penicillins and the like, have zero effect, fyi as they work on a totally different destruction mechanism than those designed to disrupt plasmid protein synthesis.

However, HERE is MY question to the experts...some one REALLY needs to tell me how is it even possible for a monoclonal antibody to "become resistent"...all the herceptin does technically is connect up like a lock and key on her-2 receptors sitting on the cell surface. As long as you are over-expressing her-2 on some of your cells, the Herceptin, should, theoretically anyway, connect to those cells and those cells alone...like a key to a lock. It is your own body's immune system that later comes along BEHIND the herceptin and cleans up the herceptin-tagged/flagged cells as NOW the supposed CANCER cells have become apparent to our immune system and as soon as the hampster- tainted herceptin smell reaches the immune patrol...it knows that something that is NOT SELF is under foot and sends in reinforcements to take out the entire HERCEPTIN tagged cell. Unless something else is already sitting on the her-2 receptors and blocking the HERCEPTIN 's docking site--which may happen in some isolated cases, I really don't think that the herceptin has "stopped" working for most folks, meaning, that as long as they STILL have over-expressing her-2, the herceptin is still going to dock with the cells that are exhibiting the over-expression, provided nothing is blocking the docking site. That your cancer may be progressing is still quite possible, but the problem is NOT WITH THE HERCEPTIN...oh, brother..I AM GOING TO GET A LOT OF HATE mail for what I am about to say next, but as this post is so long...most folks won't read this far down..hee hee... so I will just say it. In practical experience...I have long -observed that it is the patient and their immune system which gives out LONG before the HERCEPTIN stops doing exactly what it was designed to do, but I see it so DIFFERENTLY from most folks.... Herceptin alone does not KILL cancer cells...although the final scientific word is still out...in my opinion, all the herceptin does is dock with and tag the cells over-expressing her-2 period dot. It is the PERSON's own immune system that has to come in BEHIND the herceptin and start using phagocytosis to eat up and clean up the lesion /tumor debris. In my opinion, we have not yet even begun to use herceptin properly...instead of being used like a class A chemo drug...it should be used more the way insulin is for diabetics...based on YOUR OWN TUMOR BURDEN as defined by how saturated YOU PERSONALLY ARE with serum her-2 tumor markers...because if you are pouring her-2 over-expressed protein into your bloodstream as I AM...you need to take ENOUGH herceptin to GET IN FRONT OF OR AHEAD of the deluge and then, you can bring it back under control and return to more maintainance dosing.

So, often, it is NOT that the herceptin has stopped working..it is just that you have MORE cells over-expressing the her-2 than the standard 2mg can hit--as 2mg is a limited substance that can only hit a finite number of her-2 over-expressing cells...LET ME EXPLAIN by using a model..what we sometimes call a "cartoon" in grad school....THIS IS VERY OVER-simplified but just to give you a mental SNAPSHOT of my idea--not proven..fyi:

Suppose that 2mg of herceptin administered every week is enough saturation to take out a finite number of up to 2,000 cells in your body over-expressing her-2. You take the herceptin, your immune system is plenty strong at first to RECOGNIZE that suddenly you have 2,000 hampsterish (smile) smelling cells in you, mount a response, administer phagocytosis and clean up the debris and wash it all out via your circulatory, digestive and lymph systems... OK...if you are on every 2- week dosing, your body must mount this attack EACH week...which means you must eat well and rest well and supplement well so that YOUR nutrient stores necessary to mount the attack are at the ready...we are all only human...it is very difficult to take the herceptin week after week after week after week...So, over time...what happens is the original 2,000 cells tagged in our cartoon by the herceptin...don't get completely cleaned up...remember, the herceptin is JUST docking with the her-2 receptors..it is NOT killing the cancer or causing the cell to commit apoptosis..., so what happens...some of the cells not taken out by your immune system start to multiply...from my tests on myself...my her-2 rate tends to double over time...faster if my body is in a stressed or weakened conditon slower, if I am fairly healthy...now suppose that instead of 2,000 cells over -expressing her-2, suppose you now have 4,000...remember that in the logic for this cartoon we stated that 2mg of herceptin has a finite number of cells that it can tag and for our purposes we set that number equal to 2,000. OK...so you go in, you take 2mg of herceptin..it tags 2,000 her-2 over-expressing cells, your weakened immune system takes out about 1500 of the 2,000 tagged ones...oh joy, guess what 4,000 minus 1500, leaves you with 2, 500 her-2 over expressing cells that may double before your next 2mg dose of herceptin..so guess what...this week you go to take your normal 2mg dose and you have 5,000 cells over -expressing her-2 and the 2mg dose tags 2,000, you have 3,000 left that may double to 6,000 before your next dose, and...WELL, you see it doesn't take much to progress using this model and the herceptin HAS NOT STOPPED DOING WHAT IT WAS DESIGNED TO DO--tag a finite number of cells over-expressing her-2--...sorry I am always so OUTSIDE the box, but this is just the way I see it.

Usually it is very easy to see in your own bloodwork that you are not getting enough herceptin to take out all your her-2 over -expressing cells...as the more cells you have over-expressing the her-2, the MORE her-2 protein will be dumped into your bloodstream..this is why it is beyond me why no one really pays that much attention to the serum her-2 numbers...these are not MYTHOLOGICAL entities playing peek-a-boo in our bloodsteams..it is my understanding that the only way this protein can increase in your blood is because you have CELLS inside you that are pumping it out....am I missing something here??? smile...

Also, as a footnote, MY CASE IS NOT STANDARD and it is important to remember, that every time I progressed, as I had BEEN off the herceptin for an extended time, and I was made to take both a prophylactic quinolone type antibiotic and a new RE-loading dose each time I got back on it and my numbers would DROP straight down by half and then, by the next week, the overall tumor burden would be manageable enough (as my original onc made a deal with me that if my numbers got to a certain number, we would return to treatment or else he would not let me go off the herceptin in the first place) that the 2mg dose in the early days, would be sufficient...however, we must also keep in mind that I may have been helping the herceptin do its job more efficiently and reducing the amount of herceptin I needed by taking the oleic acid rich supplements, keeping my immune system strong by refusing drugs like chemo, ativan, and benedryl, and by walking a LOT, and eating right and getting adequate rest. Plus, as a single mom with a tremendous zest for life, I was VERY motivated to live...sometimes, no matter how sick you are, that hard core motivation to survive is the single most important factor in doing just that..surviving.

It was also interesting to note that my cancer would progress more quickly every time I over-extended myself with my work or research or social activities...it was very important to maintain adequate rest and exercise at all times...that is why I had to learn over years of trial and error to rigidly adhere to my base regimen, even though I am somewhat of a free spirit and am not by nature, very disciplined...but having her-2 GAVE me no choice.

BOTTOM LINE: Before I would just randomly assume or "GUESS" that the herceptin wasn't working, I would do TWO THINGS: First, I would have my serum her-2 tumor marker levels checked several times to see where they were and if they were higher than 10, I would assume that I had cells in my body that were over-expressing the her-2 protein and dumping it into my blood at levels high enough for me to measure which would be a STRONG indication that I had cells over expressing her-2 in me. Once I empirically established active her-2 cells inside me, and was sure that my health and immune system were generally good and if my muga permitted it, I would ask for a higher reloading dose of herceptin, and hit it while continuing to take the markers..and follow through with as many consecutive dosings of herceptin as necessary to bring the serum her-2 numbers down into the single digits--and if the markers were way high...I would return to weekly or bi-weekly not every three weeks, until I could get ahead of the NUMERIC tumor progression, then attempt to return to herceptin maintenance--which can be more spaced out...once the markers consistently were under 10...BASIC CONCEPT: before trying anything else and certainly before ADDING an immune depleting chemo..I WOULD INSIST on being treated with more herceptin more frequently to see if you could drop the tumor burden and return to NED. IF that did not work, and if your GRANS were very high, over 80, I would consider adding micro taxol to knock way down the grans (neutrophils which may be propagating the her-2 mediated disease--I also would not under any circumstance take neulastin or any other drug designed to INCREASE neutrophils..fy), but I would do a lot of zinc and good nutrition and supplementation to keep the rest of the body intact and supply the immune system with every nutrient it needed to launch a full- scale attack on lots of her-2 tagged cells as in my model...it stands to reason that if 2mg of herceptin can hypothetically tag a finite number of say 2,000 over -expressing her-2 cells, then 4mg could hypothetically tag MORE, say double = 4,000 her-2 over-expressing cells, and 6mg could tag 6,000, and 8mg could tag 8,000, etc--for example, the real numbers are probably much MUCH HIGHER.

In fact, I have always been amazed that they give you a LOWER dose of herceptin after the first loading dose rather than the other way around...as it seems counter intuitive for a disease we all know tends to progress. For instance, I think it would be interesting to see a trial of 2mg the first week, followed by 4mg the second week, followed by 6mg the third week...of course, the worry is that this would be too hard on the heart--but if it could be proven that say the 2mg per week dosing of herceptin actually does just hit a finite number of cells, why not just give some of us with really bad mets a heavy 12mg from the start??? and see how long it is from mega hit to progression? I personally, would LOVE to volunteer for this, but alas, I am a poor test subject as I don't take direction very well...but I think herceptin has been proven safe for up to 14mg, but I am not sure. If my model of limited herceptin dosing hitting a finite number of cells is right, why are we wasting time and MONEY with all this 2mg stuff...when many of us are exhibiting serum her-2 levels over 500, even over 1,000. Anyway, it does not make good scientific sense to me, but from a business perspective of course, it is only logical...smile.

Anyway, the zinc will also especially boost the lymphs which have an inverse relationship to the grans...you want your lymphs high, and your grans LOW. This will also give you good energy flow. And anyhow, there may be a much SIMPLER solution to the whole problem than screwing around with the Herceptin dosing as the herceptin is merely hitting the her-2 which is already way DOWN stream from the source of the problem, but that is a story for another day off...smile.

In the final analysis, I am only a patient...what could I POSSIBLY KNOW???????.........................smile,
Gina

Creme de la creme - Gina. I printed this and put it in my keeper file so in 20 years, I can fax it back to you and say "see, see - I told you that you posted incredible emails that printed to 4 sheets".


There is no resistance to Herceptin. I agree with this. I also agree that there are some dose dependent aspects to Herceptin - especially much more so in metastatic disease where there is tumor load (versus the adjuvant - early breast cancer setting). However, after my first loading dose, I wore heavy clothes, shoes, coat, purse and book bag. Nobody caught on. (No I don't get that much extra but my new (and much more observant onc) did comment that I lost 8 lbs in 6 weeks (I didn't but "I did"). Now I am really on the 6mg/kg dose every three weeks (and another reason why I started the first 12 as weeklies - "really putting on the weight" during these 12). Now I am what I am on the every three week. But, one is not getting that much more "weighing" 12-15 lbs more.

Again - resistance - part is the increasing tumor load versus the herceptin dose (and your description is perfect). Another is that life (even life we want to die) finds a way. What I mean is the downregulation of Her2 and the upregulation of - you name it - ER, PR, Her 1, EGFR, Her 3, Her 4 and all others that we know and don't know. Therefore, there is no Her2 to tag or very little (especially for a weakening immune system to find). Hence - during new recurrences, get your tumor tested again and make sure it hasn't dramatically changed!!! Or of course is that some cells have lots of Her2 receptors and some have just alittle bit. You kill the ones with lots and the only ones left to reproduce are the ones with less (or something else that's different that effects proliferation rate - Darwinism at its finest (another fav topic of mine)).

Also - how does Herceptin work? I think like you said - tagged cells are destoryed by the immune system. I also think it could work by tagging the receptors so they can't bind with the growth hormone and grow out of control. The growth receptor mechanism is blocked. However, the cell does not die - it dies a natural death. The question is when. I think sometimes the time was near anyway. But if it is a young cancer cell, it may hang around a long time and the tagging of herceptin is a surface phenomenon (remember - I sell surfactants for living an acronym for surface active agents) and surfaces interacting with one another is not a permanent situation. How long does the surface interaction occur? It is key and lock but is the fit tight? Is the fit tighter for you than for me (because of genetic and biochemical makeup?) Is it tight if I keep my omega 3/6 in balance, eat tumeric with vitamin C, without vitamin C (is this why Herceptin works better for some than others - the fit is tighter - there is less migration from the cell surface? I am just playing devils advocate here but I think you know what I mean. Or just that Herceptin comes off the surface before the immune system finds it to destory it with the cancer cell still attached?

Neulasta - I took Leukine during dense dosing because it boosts the macrophages (monocytes and dendrites too) and has protective effects on the lymphs (see www.leukine.com) Someone once told me that Neulasta might actually be proven to do more harm than good one day. But the oncs love it because they want to see the neutrophils and they are heavily entertained by Amgen. I am not a proponent of neulasta (or procrit either).

Well, Gina, the Hungarian enthusiasm has been lit this afternoon. Certainly, I will think of more later as I am at work now and want to maintain employment.

Bestest regards

Becky

Drug resistence doesn't mean the drug doesn't work, it just means that the drug is not responding as well as planned or desired. That's certainily the context in which I intended in my abov post.In other words, Herceptin resistence implies that it has less of a response, note that doesn't mean it is not effective at all. Obviously, Herceptin becomes less effective for a reason, I don't know that the all and all answer is due to overload of her2 tumor burden. Perhaps, as Becky has mentioned the tumor cell can manipulate other pathways as a means of survival when one is becoming less responsive to Herceptin. I am not sure what article it was, but I did recently read that increased levels of her3 in bc cell lines decreased herceptin response after a time, or at least that was the implication. I don't know what the her2 serum levels were in these studies though.

Gina I always find you post very interesting with your do it yourself methods of treating her2 which I admire and respect.I also agree with one of your previous post that there should be a blood her2 monitor something like what diabetics use for monitoring insulin. You certainly have a courageous and novel approach to taking Herceptin.

I would like to point out one thing that is rather interesting with your response to Herceptin. I hope you don't mind, my mentioning it is in the hopes of us all gaining more knowledge. You are premenopausal, as I hote here and on other posts and are er- and pr-. Do you realize that prolonged Heceptin therapy can reverse the estrogen receptor? I think Lani posted that article. In that study, at 9 weeks and thereafter, certain her2+ individuals had become estrogen positive. I suppose you want to keep your negative hormonal status as you have stated before that you were happy to be enjoying your hormones still. Perhaps your short duration of Herceptin therapy has done just that for you. Anyway, best of luck. PS.I take vit A too to help bind up the estrogen receptor just in case Herceptin clicks on the estrogen receptor as I am er-,pr- too and not on any anit-estrogen.

Best to all,

RobinP

And more thoughts.....................
 

Just wanted to add as an after thought. What about those people who are her2 positive and have the truncated form of the receptor, p85. As you know that form of her2 does not have the cleavage for herceptin to fit in. So I wonder if Herceptin works at all in this case? I wonder how ip85 gets activated at all if it can not heterodimerize and what is the prognosis of p85? I think I heard on a SABC live webcast that about 25% of the early stage her2+ have p85 form of the receptor.

oh boy! all your input is making me think so much to get the second year of adjuvant Herceptin. The only reason I am afraid to stop with one year is at my initial diagnosis my supraclavicular node is positive which puts me at high risk. But my oncologist doesn't want to give me herceptin for the second year and so I am trying to get it through another oncologist. I am really worried now whether it is an intelligent decision.

thanks,
Julie

We may have results of 2 years of herceptin efficacy from the ACSO meetings this spring. Perhrps you want to decide then your duration Julie.

Robin


Good thought to remind us of the P85 angle. Susan Love's site does mention that the Her2 receptor in some women can be "damaged" or non functioning. P85 could be responsible for that. However, if the receptor is different (or deformed and herceptin does not fit in lock and key) does the protein (which is also a lock and key mechanism)? According to some literature (and a reference to that on the Love site), individuals with deformed receptors don't have the same (negative) Her2 prognosis. (Then one has to think that if those with deformed receptors have nothing to worry about but were in the early herceptin adjuvant trials, then, theorically they would not recur as readily since the Her2 mechanism was not relevent. And if they were hormone positive and on a hormonal, that would be all they needed. However, if they were hormone negative and Her 2 could not be their problem, then something else was driving their cancer to grow. Hence, some recurrences may not be due to Her2 and early herceptin could be working better than we think.

Just talking out loud here.

Have a great Saturday night.

Becky

I hate to say this but I heard via the SABC that p95( excuse me not 85 but p95) has a worse prognosis.See below article:
p95HER-2 Helps Predict Breast Cancer Outcome, Oregon Health & Science University Cancer

Category: Breast Cancer News
Article Date: 16 Jan 2006 - 0:00am (UK)[img]images/blanktab.gif[/img]

Oregon Health & Science University Cancer Institute researchers have identified a protein fragment in some human breast cancers that may help predict a patient's chances of survival.

The presence of the fragment, called p95HER-2, in breast cancer tissue correlates closely with lymph node metastasis and earlier recurrence of the disease, suggesting that p95HER-2 is a marker and perhaps even involved in metastasis.

"By studying this marker we have a better chance to identify the patients who are more likely to have a longer disease-free survival," said Edward Keenan, Ph.D., one of the authors of the study. Keenan is professor of physiology and pharmacology and associate dean for medical education, OHSU School of Medicine.

The study, conducted in the lab of Gail Clinton, Ph.D., professor of biochemistry and molecular biology, OHSU School of Medicine, in collaboration with Keenan and investigators in Spain led by Jose Baselga, M.D., will be published on Jan. 15 in Clinical Cancer Research, a journal published by the American Association for Cancer Research.

The study builds on observations the investigators have published over the last five years about the role of the HER-2 oncogene in breast cancer. HER-2, a growth factor receptor, is overexpressed in 20 to 30 percent of breast cancer cases, but it has had limited usefulness in predicting clinical outcomes, particularly in early-stage breast cancer.

Clinton's lab identified a fragment of full-length p185HER-2 that results from HER-2 cleavage, called p95HER-2, and developed an antibody that recognized it, making it possible to study the role of p95HER-2 in the spread of breast cancer.

The researchers studied breast cancer tissue from 483 biopsies from hospitals in the United States and Spain representing all stages of the disease. Two forms of the HER-2 protein were investigated: the full-length p185HER-2 receptor and its truncated form, p95HER-2. Only the truncated form proved to be a significant independent prognostic factor regarding clinical outcomes.

"More work is needed to determine if the presence of p95 has any significance regarding responsiveness of the cancers to chemotherapy, anti-estrogen therapy or Herceptin [a drug therapy for HER-2-related metastatic breast cancer]," Keenan said. "Hopefully, understanding the significance of this marker will help us better specify effective therapy for individual patients."

And another article that discusses resistence of Herceptin associated with IGF:




[im Articles by Albanell, J. [img]/icons/shared/misc/arrowTtrim.gif[/img] Articles by Baselga, J. [img]/icons/shared/misc/arrowTtrim.gif[/img] Articles citing this Article [img]/icons/spacer.gif[/img] PubMed [img]/icons/spacer.gif[/img] [img]/icons/shared/misc/arrowTtrim.gif[/img] PubMed Citation [img]/icons/shared/misc/arrowTtrim.gif[/img] Articles by Albanell, J. [img]/icons/shared/misc/arrowTtrim.gif[/img] Articles by Baselga, J. [img]/icons/spacer.gif[/img] Related Collections [img]/icons/spacer.gif[/img] [img]/icons/shared/misc/arrowTtrim.gif[/img] Journal of the National Cancer Institute, Vol. 93, No. 24, 1830-1832, December 19, 2001
© 2001 Oxford University Press
EDITORIAL

Unraveling Resistance to Trastuzumab (Herceptin): Insulin-Like Growth Factor-I Receptor, a New Suspect

Joan Albanell, Jose Baselga Affiliations of authors: J. Albanell, Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona, Spain; J. Baselga, Medical Oncology Service, Vall d'Hebron University Hospital, and Universitat Autonoma de Barcelona.

Correspondence to: Jose Baselga, M.D., Medical Oncology Service, Vall d'Hebron University Hospital, Paseo Vall d'Hebron 119–129, 08035 Barcelona, Spain (e-mail: baselga@hg.vhebron.es ).

Trastuzumab (Herceptin) is a humanized antibody directed against the extracellular domain of the tyrosine kinase receptor HER2 that has shown clinical activity against HER2-overexpressing breast tumors (1–4). HER2, the targeted receptor, is a member of the epidermal growth factor (EGF) receptor family of receptors, also known as the type I receptor tyrosine kinase family [for review, see (5)]. HER2 is overexpressed in 25%–30% of breast cancers, and its overexpression is associated with a high risk of relapse and death (6). In this group of tumors with unfavorable prognosis, trastuzumab has been a valuable addition to standard therapy, with the pivotal studies demonstrating a clear survival benefit (2,3). However, even in the selected group of patients with very high levels of HER2 overexpression who derive the greatest benefit from trastuzumab therapy, the response rate from this highly specific, targeted agent is limited in magnitude and duration (7).

This observation leads to the fundamental questions about the mechanism of action of trastuzumab in HER2-positive breast cancer cells and how these cells escape from its antitumor effects. The answer to these questions is particularly challenging because the mechanisms of action of trastuzumab have not been characterized fully and appear to be complex [for review, see (8,9)]. To date, the known mechanisms of trastuzumab's action include decreased expression of HER2 from the tumor cell surface (10), initiation of G1 arrest and induction of the cyclin-dependent kinase inhibitor p27Kip1 (8), prevention of HER2 cleavage (11), inhibition of angiogenesis (12), and induction of immune mechanisms (13). Alterations in the HER2 receptor or in downstream signaling pathways that mediate any of these effects may be responsible for some cases of primary or acquired resistance to trastuzumab. Possible mechanisms could be expression of truncated HER2 receptors that cannot bind antibodies, mutations of downstream molecules (i.e., ras activation or PTEN deletion), a low level of p27Kip1, and a decreased immune function in patients with advanced breast cancer.

Resistance to trastuzumab, however, may not only depend ultimately on its efficacy (or lack of efficacy) in inhibiting HER2 but also on whether HER2 activation is responsible, single-handedly, for the sustained growth, proliferation, and survival of a well-established tumor. In this regard, it is highly unlikely that a single, active tyrosine kinase receptor or intracellular tyrosine kinase may be solely responsible for a malignant phenotype (14), although a notable exception to this rule may be the critical role that the BCR-ABL tyrosine kinase plays in chronic myeloid leukemia and the high response rate of this disease to STI-571, a specific inhibitor of the BCR-ABL kinase (15). The emerging single-agent efficacy data with trastuzumab and other antigrowth factor receptor agents in epithelial tumors are demonstrating modest response rates, further supporting the theory that targeting just one receptor may not be enough to optimize responses (16). Furthermore, HER2 is a receptor without a cognate ligand, and transactivation of HER2 by other members of the EGF receptor family is important for the growth of HER2-overexpressing breast cancer cells. As a result, combined therapies with trastuzumab and a specific inhibitor of the EGF receptor tyrosine kinase result in enhanced growth inhibition and apoptosis (17–20).

The report by Lu et al. (21) in this issue of the Journal represents a further step ahead to unravel resistance to trastuzumab because it provides evidence for a critical role of insulin-like growth factor-I receptor (IGF-IR) signaling in the response to trastuzumab. The IGF-IR is a transmembrane tyrosine kinase receptor that is activated by binding of the IGF ligands. The hypothesis that IGF-IR signaling could influence the response to trastuzumab was raised from an extensive body of data indicating that this receptor plays an important role in breast cancer [reviewed in (22)], as follows: IGFs exert proliferative and antiapoptotic effects in many breast cancer cell lines (23,24), targeted disruption of the IGF-IR with anti-receptor antibodies or antisense RNAs to this receptor limits breast cancer proliferation, the IGF-IR and its ligands are expressed in many human breast tumors, and high levels of circulating IGF-I predict an increased risk of breast cancer in premenopausal women (25).

Lu et al. (21) have demonstrated that an increased level of IGF-IR signaling adversely interferes with trastuzumab's action on cell growth. They used two human breast cancer cell line models complementary in terms of IGF-IR expression—MCF-7/HER2-18 cells, which overexpress HER2 by transfection and endogenously express activated IGF-IRs, and SKBR3 cells, which endogenously overexpress HER2 but express few IGF-IRs (about 10% the number in MCF-7/HER2–18 cells). In MCF-7/HER2-18 cells, trastuzumab inhibited growth only when IGF-IR signaling was blocked by cotreatment with the anti-IGF-IR antibody [img]/math/alpha.gif[/img]-IR3 or the IGF-binding protein-3 (IGFBP-3). In contrast to the basal resistance of MCF-7/HER2-18 cells to trastuzumab, SKBR3 cells, which have a low level of IGF-IR expression, were sensitive to trastuzumab. Additional compelling evidence to link the IGF-IR to the trastuzumab response was provided by the observation that SKBR3 cells became resistant to trastuzumab when cells were genetically altered to overexpress IGF-IRs (SKBR3/IGF-IR). Addition of IGFBP-3, which decreased IGF-IR signaling, restored the ability of trastuzumab to suppress growth. On the basis of these studies, Lu et al. (21) appropriately propose that strategies that target IGF-IR signaling may prevent or delay development of resistance to trastuzumab. A link between IGF-IR signaling in the modulation of response to monoclonal antibodies has been shown also for the EGF receptor, which is closely related to HER2. In this regard, a recent study (26) has shown that IGF-I signaling temporarily prevented the apoptosis mediated by the anti-EGF receptor monoclonal antibody C225 in the EGF receptor auxotroph cell line DiFi. It is interesting that such inhibition was sensitive to an inhibitor of the phosphatidylinositol 3-kinase (PI-3K)/Akt pathway (26). Because the PI-3K/Akt pathway is poorly suppressed by trastuzumab in breast cancer cells (17), it is tempting to speculate that this pathway may play an important role in the observations by Lu et al (21).

What are the molecular signaling events underlying the interference of IGF-IR signaling in trastuzumab response? Lu et al. (21) characterized opposing effects of trastuzumab and IGF-IR on p27Kip1. The induction of p27Kip1 by anti-HER2 antibodies contributes to their effects on growth inhibition (8). However, in SKBR3/IGF-IR cells, the baseline levels of p27Kip1 were very low compared with those in SKBR3/neo control cells, and trastuzumab could not induce p27Kip1 expression. This effect might be mediated by interference between the IGF-IR and HER2 in signaling pathways that regulate p27Kip1. Such downstream pathways include ras/raf/mitogen-activated protein kinase or, as mentioned above, PI3-K/Akt signaling, and it would be of practical interest to characterize this possibility because we have inhibitors of these pathways in clinical development. In addition, because IGF-IR signaling has been linked to antiapoptotic effects and resistance to several anticancer treatments (22,26,27), it would be relevant to study whether IGF-IR targeting when combined with trastuzumab results in an enhanced apoptosis. Searching for interactions between both receptor systems will not be an easy task, because diverse study models have revealed different hierarchical cross-regulations between HER2 and the IGF-IR (28,29).

It is evident that trastuzumab development has been a model of a rationally designed targeted treatment, where laboratory predictions have been followed by remarkably successful clinical studies. There are, however, many unanswered biologic questions regarding the mechanisms of action of trastuzumab and causes of resistance to this antibody that warrant further investigation. In the meantime, the study by Lu et al. (21) sheds light on a potential strategy—the inhibition of IGF-IR signaling—to prevent or reverse resistance to trastuzumab. Based on the results obtained by Lu et al., it would be important to characterize the coexpression of HER2 and members of the IGF-IR signaling pathway in breast tumors. In particular, analysis of baseline breast tumor biopsy specimens from patients treated with trastuzumab would provide critical insights into the possible role of IGF-IR in primary clinical responsiveness to the antibody. If an association between IGF-IR activation and resistance to trastuzumab were established in the clinic, it would be a strong signal to combine anti-IGF-IR and anti-HER2 therapies in patients with breast cancer.

REFERENCES

Although I know this thread was not...
 

every one's cup of tea due to its somewhat technical nature..I just wanted to say..the high level of exchange of ideas of free flowing brain-storming was superb.

I would love to get together in person with all who contributed sometime just to brain storm about these and so many other her-2 related issues.

Robin, in the early days, as Herceptin was so new and "resistance" to more traditional chemos quite common..., I must confess, that one reason I hesitated to take more herceptin than absolutely necessary was just that...I was worried about potential "resistance" no matter how you define that. The other reason was in the early days, no one really KNEW for sure what all the possible side effects of taking herceptin would eventually turn out to be, and as most of us were figured to be dead in a month or two anyway..NO ONE EVEN TALKED about the long - term side effects.

Fortunately, as we all know, the science behind HERCEPTIN was very sound and actually, thankfully, I encounter very few folks who really have any major problems caused by the herceptin. However, even early on, besides heart issues, there was another concern about herceptin's possible negative effects on the reproductive tract as in pelvic mets and increased CA 125's which as you know are often indicative of ovarian cancer. I only learned this early on because one of the gals who was detailed to do my complicated blood draws had been working as a cancer tumor marker researcher in a major research hospital where herceptin was being tested in various ways and one of the "complications" that kept showing up was an increase in CA 125 for women taking herceptin over extended periods of time...although, interestingly, at least in the group being studied...this increase in CA 125 did not always progress to ovarian cancer...but was common enough as were "PELVIC METS" to be noted.

Over the years, especially when I would take some herceptin in a row, I would get from time to time "complex" cysts on my ovaries. This worried me to no end. So much so, I even agreed to exploratory surgery, knowing the risks of worsening mets that often accompany surgery. What they found and took plenty of color pictures of ... was a perfect internal reproductive anatomy...absolutely perfect...samples taken everywhere revealed INFLAMATION but no cancerous or even pre-cancerous cells..., but unfortunately, no "cause" of the inflamation and highly vacuolated cells could be determined via pathology.

The color shot of my liver, which of course, was metastatic at the time...revealed the unexpected white lace -like patterns of the nearly 2-D Her-2 lesions that were there at the time...resting gently on a bed of otherwise absolutely red and healthy liver. It was so healthy, the surgeon, knowing of my past history with 12 metastatic liver lesions, could not believe its fortunate condition.

As for worrying about my ER-PR- cancer turning hormonal positive...it is strange that from my her-2 mediated disease, I worry more about what will happen to me when I enter natural menopause, as in my case, my continuing to produce estrogen has been one of the number one KEY factors that help keep my brand/variety of her-2 in control...I tested this many times, by seeing my markers slightly rise as my estrogen levels would drop before my cycle...also, when I had my primory 5cm tumor...even though none of my doctors would listen to me...it got much worse and grew more the week BEFORE my period as the estrogen levels dropped...you see, I have a completely different theory of estrogen from most folks in the cancer world. I actually think it is a good thing with my type of her-2 as estrogen has an inverse relationship to her-2...at least in my body--but is documented also in the literature...when estrogen is at normal levels (not excessive as I have never had that problem), but when they are at normal levels..her-2 tends to stay in check...when they drop, that is when I have to work harder to keep the markers down...

I have said this before, but I do believe a good percentage of us on this site share a common ancestor that goes WAY back to the early pre-out-of Africa settlements in eastern europe...we can trace our lineage back to a time when there were no grandmothers --to a time of perhaps something like a self-destruct gene..a time when "hominids" resembled their cousins much more closely, meaning that once the time of reproduction had past, so had bio-chemical usefulness and thus, early death was just the natural order of life. Once estrogen levels started to drop, the her-2 would become unchecked and relatively quickly, the 30-something female would simply expire. For a long time I looked at her-2 as a remnant of some sort of self - destruct mechanism, but now I am not so sure. Still, for me, I progress less actively when my own estrogen is not inhibited. I progress moreso when it is chemically inhibited..as I did at various times in 1997 and 1998 while taking very high doses of CAF and taxotere...which AS MANY OF US on this site "know" causes chemically induced menopause...naturally as I was so young back then...once the chemo stopped...everything just went back to normal..my periods are regular and mostly like clockwork ever since.

So although I realize I am THE ABSOLUTELY ONLY person in the world who finds estrogen with her-2 a very USEFUL combination..smile..I will just stop before the tomatoes start to be thrown at me...smile.

As far as to using herceptin differently from most folks, you have to understand that above all things I consider myself an independent thinker and do not bend easily to the opinions of others..nahhhhh...giggle...giggle....even though many times--in many areas of my life..not just cancer, I have had to pay a very high price for this free thinking, so when my first onc saw the liver spots and told me I would be dead in about 2 months and to find a family for my son to live with and put all my affairs in order...I had difficulty believing "HIS VERSION" of reality as I sat there holding a PERFECT blood chemistry in my hand...and apart from a severely inflamed liver that was causing me serious digestive difficulties, I felt--as strange as it is to say...that my general constitution was perfectly HEALTHY and some how in balance and my intuition told me that what I was fighting was a much more LOCALIZED event than the terms metastatic cancer tend to suggest...which really means, of course, systemic. So I had a real difficulty merging the reality of the "world view" of my onc with the reality of what my own body was telling me....I also had a REAL problem with the theory "that MY genes were all messed up and this is what was causing my cancer"...for many reasons, it just did not "seem" to me to be the case. Anyway, no one will understand what I am trying to express, but somehow, I just thought that something else -- an outside force, an external first cause-- was at work here and I worried that like Helen Longino's LANDMARK work, "Science as Social Knowledge" maybe the entire cancer paradigm was based on one or two terribly wrong first assumptions, and because we were all so embedded in the paradigm we just couldn't see it. So, like Ockham's razor, I decided, then and there, that I would do the best I could to wipe my mind clean of everything I had ever heard, read, learned or been told about all that it means to have cancer and I would start fresh, using my own life experience and my own blood work as my lab.

What I found was pretty much any thing we had be led to "believe" about cancer, did not hold up to empirical testing and measuring...with very little effort and very few resources, I found that I could pretty much find at least ONE FALSE example of every TRUISM ever taught about this hideous disease...to me, the empirical data and my own poignant reactions to my experiences and later from the detailed observations of others with her-2 and other cancers became my only truth. I pig-headedly and dogmatically began to follow a very simple and pragmatic path. If something "worked" and could be tested and measured and proven of benefit, I continued with it. If I tried something, no MATTER HOW FABULOUS it was "believed" to work against her-2 or cancer, if it brought me personally no benefit that could be measured, I didn't waste my time, energy, or money. If I tried something that outright made me worse or nearly killed me (this happened on occasion as you must remember I tested many things early on BLINDLY), well, I just simply didn't test them or use them again, this included saying NO to more typical "chemo" concoctions and combos that onc after onc would offer me again and again and again...sighh... as I said above, I told my first onc after the first rounds with chemo which only bought me about 5 months of remission that, "Even if I died, I would not follow that route again." WHY?? because...HELLO...obviously, it didn't work for me.

Herceptin, of course, offered a completely different mechanism of action, one that was much more complementary to my style and way of thinking. For me, personally, someone with a history of robust health and ultra - high energy levels with an equally active child to raise alone, the price chemo levied, was way too high...also remember, chemo today, is not at all like it was back in 1997...I understand today the dosing is lower and there are more 'drugs' to control the nasties...not sure that is a good thing, but it is what it is.

Besides, I was still young and optimistic. I had very much wanted a large family as I am crazy for kids and get along well with them as I am just an over-grown one myself... I could not bear parting with my reproductive capability and besides I told myself, even back then...just wait it out...they have already invented herceptin...surely the next "BIG" breakthrough will be long before my biological clock ticks its last tock..., but...I was wrong...I waited 6 years from November, 1998 when Herceptin was first approved by the FDA until late in 2004 it sadly began to dawn on me that I was turning 40 in that same year, and though happy that I was to be doing so, I realized that my clock was nearing its last tock and that for me, there not only would be no cure to arrive like a super hero in the nick of time to save the day, but worst of all no daughter to beget...something given my heritage and the importance of passing on my mitochondrial DNA that was very important to me...just another thing in a long line of so many, that having her-2 mediated disease had taken away from me. But worst of all, as bad as having this disease was for myself..., what I could not get off my mind was the horrors it was doing to others in my 'clan' others like me...perhaps, going way back...even others of my own blood. I often thought on that quote originally from Plato I believe about the sacrifice of the one for the many, but if you are already on the her-2 fast track to destination death, it becomes not a sacrifice, but merely the only path unbarred.

It is now 2006. In a few more days, I will turn 42. I am profoundly grateful at my nearly unprecedented her-2 longevity, but at the same time, dismayed that now even two MORE years have passed, and yet, I find myself still tethered to the exact same spot, dragging my Herceptin infusion behind me.

We can not keep waiting. We must come together and solve the puzzle for ourselves. If we wait for science, as a very wise man, Stu Kaufman, author of "At home in the Universe" and the key promoter of complexity theory and self-organization of matter once predicted, it could take another 20 years.

I have lost nearly a decade to this disease. I will not stand by silently for 2 more. There has to be a better way. There is and together we can find it.

OK..ok...more tomatoes..ooh and rotten eggs..smile...time to say goodnite,
Gina

grandmothers
 

Gina,
In a very fascinating article in The Economist they speculated that humans are the only species where the female survives substantially beyond reproductive age is due to the importance to the species of the contribution made by grandmothers--including freeing up their daughters to have more energy to produce more grandchildren.


I have not contributed to the species by being either a mother or a grandmother, so who am I to contribute to this topic further?

Enough tonight for evolutionary thinking!

just to add more complication in a similar vein to Gina's musings...
 

The relationship between ER and her2 is still being discovered. A most interesting article hot off the press:

1: Mol Cell. 2006 Feb 3;21(3):393-404.
Links

Combinatorial Analysis of Transcription Factor Partners Reveals Recruitment of c-MYC to Estrogen Receptor-alpha Responsive Promoters.

Cheng AS, Jin VX, Fan M, Smith LT, Liyanarachchi S, Yan PS, Leu YW, Chan MW, Plass C, Nephew KP, Davuluri RV, Huang TH.

Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210.

In breast cancer and normal estrogen target tissues, estrogen receptor-alpha (ERalpha) signaling results in the establishment of spatiotemporal patterns of gene expression. Whereas primary target gene regulation by ERalpha involves recruitment of coregulatory proteins, coactivators, or corepressors, activation of these downstream promoters by receptor signaling may also involve partnership of ERalpha with other transcription factors. By using an integrated, genome-wide approach that involves ChIP-chip and computational modeling, we uncovered 13 ERalpha-responsive promoters containing both ERalpha and c-MYC binding elements located within close proximity (13-214 bp) to each other. Estrogen stimulation enhanced the c-MYC-ERalpha interaction and facilitated the association of ERalpha, c-MYC, and the coactivator TRRAP with these estrogen-responsive promoters, resulting in chromatin remodeling and increased transcription. These results suggest that ERalpha and c-MYC physically interact to stabilize the ERalpha-coactivator complex, thereby permitting other signal transduction pathways to fine-tune estrogen-mediated signaling networks.

PMID: 16455494 [PubMed - in process]

Lots still to unravel!

PPAR gamma
 

Lani,
Fascinating posts you have obviously been busy looking at the subject generally.

The whole subject of fats, BC, herceptin, insulin usage, diabetes, coronary and vascular health, all seem to have some common connections is this hugely complex puzzle.

My own definately non expert suggestion is that the omega three six balance is a magor factor, and that cutting down in omega six is key. I am not sure where oleic acid fits in, but the usage of quality olive oil instead of high omega six sources could be a factor as could any inherent properties of oleic sources.

I have only skimmed the above and will come back on it.

Both omega three and six are closely linked to the PPARs. I need to re-read the bits I have saved. Why a fraction of the funds that are put into the development of drugs could not be put into looking at dietary factors is my question. Did anybody see the reports that diabetes in Harlem is heading to an appearance in one person in five. PPAR is also mentioned in relation to diabetes.

As a start in relation to the post on PPAR gamma above here is a link on PPAR gamma. The article calls PPAR gamma "A MASTER REGULATOR OF THE FORMATION OF BODY FAT" .


http://www.salk.edu/news/releases/details.php?id=54

Salk Scientists Identify Molecular Link Between Dietary Fat And Colon Cancer

July 31, 1998
LA JOLLA, CA — Although it's now common wisdom that dietary fat is related to some cancers, medical researchers have not understood the underlying mechanisms. In research reported in the September 1 issue of Nature Medicine, scientists at The Salk Institute for Biological Studies identify a molecular link between fat metabolism and colon cancer. The results may also be relevant to breast and prostate cancer, common cancers that are also associated with dietary fat.

"The identification of a specific molecular fat sensor that contributes to human cancer provides us with a direct opportunity to develop new classes of pharmaceutical drugs," according to Salk Professor Ronald Evans, senior author of the study.

The link, a molecule named PPAR gamma, was shown in previous work from Evans' laboratory to aid in the formation of fat cells and storage of fat. In the current study, mice given compounds known to stimulate PPAR gamma developed three times as many colon polyps as their litter mates. The strain of mice used in the experiments are predisposed to develop colon polyps and are frequently used as a model for human familial colon cancer.

On the molecular level, PPAR gamma acts as a fat sensorÑhormones, drugs, and dietary fats attach to the sensor to exert their influence. Earlier work had shown that PPAR gamma and its hormone serve as a master regulator of the formation of body fat.

The current study used synthetic hormones to attach to PPAR gamma; mice given these hormones developed polyps at a rate comparable to mice in other studies that were maintained on high-fat diets.

"The results are highly suggestive of PPAR gamma mediating the connection between fat intake and cancer promotion," said Enrique Saez, postdoctoral fellow and lead author of the study. "Presumably fat stimulates PPAR gamma to regulate genes that control cell division, cell death or other aspects of tumor development. The next step is to identify these genetic targets."

Because PPAR gamma also is found in breast and prostate cancer cells, the investigators believe the current study has implications for understanding the link between dietary fat and these two common cancers.

In addition to their relevance to tumor development, the findings raise questions about medical treatments currently used for diabetes. Troglitazone, marketed as Rezulin and one of the most commonly prescribed drugs for non-insulin dependent diabetes, stimulates PPAR gamma and is the same hormone used by the Evans group.

"These findings raise the issue of whether troglitazone treatment might increase risk for colon cancer," according to Peter Tontonoz, M.D., postdoctoral fellow and a co-author of the study. "It's an issue that should be examined, particularly in patients with a family history of colon cancer."

He added that troglitazone treatment did not increase colon polyps in normal mice and therefore might not present a risk to diabetes patients with no family history of colorectal cancer.

Paradoxically, when the investigators treated colon cells in tissue culture with PPAR gamma stimulators, tumor cells actually lost some of their cancer-like properties and began to revert to normal. A research group from the Dana Farber Cancer Institute in Boston reports similar results with cultured cells in the same issue of Nature Medicine and advocates using PPAR gamma stimulators to treat colon cancers. "We're not sure why we should see this conflict between the in vitro and in vivo results," said Evans. "But we believe that the animal results are probably more relevant to what goes on in human beings and caution against using PPAR gamma stimulators in humans."

A third paper in the journal from a team at Institut Pasteur in Lille, France reports results in mice that agree with the Salk findings. Salk co-authors include research technicians Michael C. Nelson, Jacqueline G. A. Alvarez and Tze Ming U. Collaborators include Stephen M. Baird, M.D., a surgical pathologist at the University of California, San Diego; and Vilmos A. Thomazy, M.D., a pathologist at the University of Texas at Houston Medical School. Evans is a Howard Hughes Medical Institute investigator, and Saez was supported by the Susan G. Komen Breast Cancer Foundation.

The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution conducting basic science research dedicated to the improvement of human health and improving the quantity and quality of the world's food supply.

Its two main fields of concentration are neuroscience and molecular-cellular biology and genetics.
###

Another trial linking omega three, PPAR gamma, and BC.

RB


ABSTRACT

1: Br J Nutr. 2002 Mar;87(3):193-8. Related Articles, Links


N-3 fatty acids and lipid peroxidation in breast cancer inhibition.

Stoll BA.

Oncology Department, St Thomas' Hospital, London, UK.

Long-chain n-3 fatty acids (FA) consistently inhibit the growth of human breast cancer (BC) cells both in culture and in grafts in immunosuppressed mice. Large cohort studies have, however, failed to confirm a protective effect for fish oils rich in n-3 FA against BC risk. The present review examines new evidence on biological mechanisms which may be involved in the inhibition of mammary carcinogenesis by long-chain n-3 FA, focusing on an apoptotic effect by its lipid peroxidation products. Dietary intake of n-3 FA leads to their incorporation into cell membrane lipids. Increased apoptosis in human BC cells following exposure to long-chain n-3 FA such as eicosapentaenoic and docosahexaenoic acids is generally ascribed to their inhibition of cyclooxygenase 2 which promotes mammary carcinogenesis. In addition however, long-chain n-3 FA are particularly likely to activate peroxisome proliferator-activated receptor (PPAR)-gamma, a key regulator of lipid metabolism but also capable of modulating proliferative activity in a variety of cells including mammary cells. Expression of PPAR-gamma in the nucleus is activated by second messengers such as J series prostaglandins and the latter have been shown to cause apoptosis in vivo in explants of human BC cells in immunosuppressed mice. In mammary tumours, it is observed that long-chain FA not only increase apoptosis, but also increase lipid peroxidation, and the apoptotic effect can be reversed by antioxidants. The rationale for use of n-3 FA dietary supplements in counteracting BC progression needs to be tested clinically in a phase 2 pilot study, while at the same time, the effect on whole-body lipid peroxidation needs to be monitored. Dietary supplements of fish oil rich in n-3 FA are proposed for premenopausal women over the age of 40 years who are shown to be at increased BC risk. Biological markers in breast tissue of BC progression will be monitored, and observed changes related to serial plasma levels of isoprostanes as a measure of whole-body lipid peroxidation.

Publication Types:
• Review
• Review, Tutorial

PMID: 12064327 [PubMed - indexed for MEDLINE]

I too have looked for trials looking at the impact of omega threes on the efficacy of herceptin.

I have looked on NCIB and cannot find anything.

I have a nagging feeling I have seen somthing but cannot recall the details, or if it related to another treatment.

If I find it I will post it.

RB

The POWER of this board...
 

is the freedom we all share to exchange ideas no matter how varied or outside the box they may be. It is only thanks to high level of trust and comfort that this board nurtures that enables many of us who would otherwise remain silent to actually speak up and sometimes, even speak out. We are so fortunate to have such a truly OPEN forum and I can not thank Christine and Joe enough for all they must do behind- the- scenes to continually provide us with such a fabulous tool.

Obviously, many of us will differ in ideology from time to time, and I admittedly tend to follow evolutionary thinking and enjoy reading folks like Darwin, Richard Dawson and Bryan Skyes and many others who share these views. However, I also read Stu Kaufman (At home in the Universe, is particularly accessible) and several varied supporters of intelligent design and was personally raised very strictly religious and protestant.

That said, almost any anthropology book that you would pick up would note that the lives of the early hominids were brief, certainly by 21st century homo sapien standards anyway...and "grandmothers" actually are a rather recent evolutionary phenomenon, one that has MOST likely--as was pointed out above, made a world of difference to our entire culture.

I will look up the studies on the inverse relationship between estrogen and her-2 and post them either here or in the articles section for any one interested...the her-2 link to a common ancestor ideas presented in my thread above were just some original research areas that if I had the time, I would enjoy pursuing..more as a hobby than serious "science"...smile... Also, it is important to remember that her-2, as a remnant of some sort of self-destruct mechanism, was an early theory that I examined and not one that I pay much attention to these days, but is still viable until proved or disproved one way or the other.

However, it is at least of passing note that a LARGE percentage of species, extinct and contemporary, die out after their reproductive capabilities have diminished in order to free up and provide space and resources so that their young might flourish. Our species found, however, ...over many, many years of evolution, that the emergence of "grandmothers" provided both significant survival advantage to our progeny and a reliable way to increase our numbers "to cover all the earth"...and this is just as true today as it was perhaps, thousands of years ago...grandmothers are a very vital link to all that we were in the past and to much of what our sons and daughters will become in the next generations.

Grandmothers to mothers to daughters pass on the mitochondrial DNA..., latest research areas of interest has been to zero- in on this mitochondrial DNA to see if it has any involvement with the her-2 cascade scenarios. And even though I tend to follow an infectuous first cause paradigm of her-2, I can not ignore the data that not only do quinolones and other certain types of antibiotics disrupt plasmid protein synthesis, but they ALSO, by virtue of the fact that the mitochondria were-- in pre-eucaryote days anyway, most likely bacteria, ..have the power to disrupt mitochondrial DNA/ RNA protein synthesis and if some part of the A to c-myc- to her-2 to Vegf to Z cascade is being influenced by these mitochondrial pathways--passed down to us from those very same great great great grandmothers, then, the disruption caused by the quinolones and other certain classes of antibiotics is what produces the positive effect in downgrading her-2 mediated disease and not because these quinolones and other antibiotics are taking out some postulated first cause air breathing gram negative organism...but, if one were to strictly apply Ockham's razor here...the infectuous first cause theory would still win out as it is the most elegant by virtue of its simplicity of the two: Take out the organism causing the cascade and entire cancer promoting machinery grinds to a dead stop, and the rest of the cell is left intact.

Pragmatism would urge us not to waste time debating the two theories as ad hoc though they may be--as the end result is more or less the same, but if, for whatever reasons the quinolones and certain anti-biotics have a measureable effect on down grading her-2, let's release that for compassionate use RIGHT now and save the splitting -hair arguments for why they work for later, but that is just me, someone who supports a common sense to science approach.

In order to ever do justice to investigating ANY of these outside -the -box original hypotheses, one would certainly require more resources than a private citizen such as myself has at this time anyway. Also, love him or hate him, even our President --in his recent State of the Union speech --was calling on PRIVATE as well as public sector involvement to get on board, regardless of partisan politics, and simply SOLVE THE PROBLEMS. The new Virginia Governor, echoed this exact same sentiment in his after remarks and is well-known to have worked hard in Virginia with former governor Mark Warner to achieve just that.

Folks, we have a multi-faceted problem here were her-2 is concerned. If proteins were bits of colored yarn..it is like we have a multi-colored, knotted wad of them to untangle before completely understanding the mechanism of her-2 mediated disease.

Let's start untying the knots and unraveling the yarn....the more of us who share what we are learning with each other on this board, just like we have been doing in this thread and so many others, the faster we can unravel the whole ball. Let's agree that not only is it OK to disagree, but that it is expected and even sought after. Nothing new and different is-- by definition-- ever created out of absolute homogeneity. Only after debating and reviewing as many angles of the issue and viewpoints as we can will the taste of ultimate consensus be obtained and made all the sweeter. I look forward to that day.

Also, on the issue of begetting and the expanded value of web-sites such as ours, I was thinking today, that in the past, the only way the DNA could be passed on was via physical direct transmission from one generation to the next and unless you passed your genes on via this route, they died with you. But then, it occurred to me that thanks to the invention of the internet, for those of us who may not be blessed to pass on our "code" in the traditional way, that sites such as these may evolve into collective knowledge repositories that in their own way will transmit "the code" of life via wisdom gained and transmitted by words rather than merely genes to future generations and that these repositories will benefit and advance our species continued survival and expansion in a way not unlike the extended benefit provided by our grandmothers. So in the final analysis, even though I may never physically be able to transmit my own mitochondrial DNA to an actual "daughter" there still remains hope that something of what my great, great, great, grandmothers passed down to me, may still live on, not in the flesh, but in the word.

"In the beginning was the word."

Godspeed,
Gina

There are theories that the mitochondrial DNA (which is vastly different than the DNA in our cells) was incorporated via a bacteria or other organism (God knows when). This happened as a positive symbiotic relationship as the mitochondria is the powerhouse work station within a cell (the site where glucose is broken down into ATP - the essence of the energy of life). Mitochondrial DNA is simple versus that of our cells. So simple that the bacteria incorporation theory was formulated.


Think of the mitochondria as the powerplant of the cell but it sings its own song versus all the cells in your body that sing a different song. However, heart cells sing a different part of that song than a lung cell than a skin cell (but it is still the same song while the mitochondrial song is entirely different in every way).

That's all for now

Becky

More on PPARs, linking cardiac health diabetes etc.
 

I have no idea how it all sits together, but the more one sees the more it is evident it all interlinks somehow and proably explains why herceptin acts also on coronary health, and for me a very personal view underlines the importance of at the least balancing the omega threes and sixes.

You will see linoleic acid features again.

RB

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum


1: J Biol Chem. 2005 Oct 14;280(41):34786-95. Epub 2005 Aug 10. Related Articles, Links
Click here to read
Free fatty acids repress the GLUT4 gene expression in cardiac muscle via novel response elements.

Armoni M, Harel C, Bar-Yoseph F, Milo S, Karnieli E.

Institute of Endocrinology, Diabetes and Metabolism, Rambam Medical Center and B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.

Hyperlipidemia (HL) impairs cardiac glucose homeostasis, but the molecular mechanisms involved are yet unclear. We examined HL-regulated GLUT4 and peroxisome proliferator-activated receptor (PPAR) gamma gene expression in human cardiac muscle. Compared with control patients, GLUT4 protein levels were 30% lower in human cardiac muscle biopsies from patients with HL and/or type 2 diabetes mellitus, whereas GLUT4 mRNA levels were unchanged. PPARgamma mRNA levels were 30-50% lower in patients with HL and/or diabetes mellitus type 2 than in controls. Reporter studies in H9C2 cardiomyotubes showed that HL in vitro, induced by high levels of arachidonic (AA) stearic, linoleic, and oleic acids (24 h, 200 mum) repressed transcription from the GLUT4 promoter; AA also repressed transcription from the PPARgamma1 and PPARgamma2 promoters. Co-expression of PPARgamma2 repressed GLUT4 promoter activity, and the addition of AA further enhanced this effect. 5'-Deletion analysis revealed three GLUT4 promoter regions that accounted for AA-mediated effects: two repression-mediating sequences at -443/-423 bp and -222/-197 bp, the deletion of either or both of which led to a partial derepression of promoter activity, and a third derepression-mediating sequence at -612/-587 bp that was required for sustaining this derepression effect. Electromobility shift assay further shows that AA enhanced binding to two of the three regions of cardiac nuclear protein(s), the nature of which is still unknown. We propose that HL, exhibited as a high free fatty acid level, modulates GLUT4 gene expression in cardiac muscle via a complex mechanism that includes: (a) binding of AA mediator proteins to three newly identified response elements on the GLUT4 promoter gene and (b) repression of GLUT4 and the PPARgamma genes by AA.

PMID: 16096283 [PubMed - indexed for MEDLINE]

Re the evolutionary theory.

I cannot comment on the impact of declining or increasing eostrogen, but I have seen articles suggesting that cancers are in part a reflection of an evolutionary response, a triggering of elemental cells in reponse to environmental stress (of all sorts including diet), and I would guess oestrogen is in there somewhere. The more I read on oestrogen the more complex it appears given the bodies ability to produce it in different ways at different sites, to store it etc. I think the trials / suggestions that in certain limited circumstances that eostrogen can work against BC, might indicate it is all a great deal more complex than we yet realise, and todays absolute views on eostrogen exclusion might become rather less absolute in the future - as to the relative merits of your discussion I simply have not read do not know enough to comment specifically.

My personal strictly amateur guess at a significant trigger is the huge excess of omega six intake, over historic levels compunded by low omega threes, trans fats, and exclusion of small amounts of traditional sources such as dairy. It is a clearly evident trend. The impact of grossly stoking the omega six emergency repair inflamatory pathways are also evident in many other related diseases, coronary, diabetes, arthritis. Fats are truly fundamental to life.

That is not to say it expalins all or is the only factor, but my hunch is it is a magor one.

RB

Peroxisome proliferator-activated receptor alpha (PPARalpha) potentiates, whereas PPA
 

Another interesting trial linking ppars to fats insulin etc.

RB

ABSTRACT

1: Endocrinology. 2005 Aug;146(8):3266-76. Epub 2005 May 5. Related Articles, Links
Click here to read
Comment in:

* Endocrinology. 2005 Aug;146(8):3263-5.


Peroxisome proliferator-activated receptor alpha (PPARalpha) potentiates, whereas PPARgamma attenuates, glucose-stimulated insulin secretion in pancreatic beta-cells.

Ravnskjaer K, Boergesen M, Rubi B, Larsen JK, Nielsen T, Fridriksson J, Maechler P, Mandrup S.

Department of Biochemistry and Molecular Biology University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark.

Fatty acids (FAs) are known to be important regulators of insulin secretion from pancreatic beta-cells. FA-coenzyme A esters have been shown to directly stimulate the secretion process, whereas long-term exposure of beta-cells to FAs compromises glucose-stimulated insulin secretion (GSIS) by mechanisms unknown to date. It has been speculated that some of these long-term effects are mediated by members of the peroxisome proliferator-activated receptor (PPAR) family via an induction of uncoupling protein-2 (UCP2). In this study we show that adenoviral coexpression of PPARalpha and retinoid X receptor alpha (RXRalpha) in INS-1E beta-cells synergistically and in a dose- and ligand-dependent manner increases the expression of known PPARalpha target genes and enhances FA uptake and beta-oxidation. In contrast, ectopic expression of PPARgamma/RXRalpha increases FA uptake and deposition as triacylglycerides. Although the expression of PPARalpha/RXRalpha leads to the induction of UCP2 mRNA and protein, this is not accompanied by reduced hyperpolarization of the mitochondrial membrane, indicating that under these conditions, increased UCP2 expression is insufficient for dissipation of the mitochondrial proton gradient. Importantly, whereas expression of PPARgamma/RXRalpha attenuates GSIS, the expression of PPARalpha/RXRalpha potentiates GSIS in rat islets and INS-1E cells without affecting the mitochondrial membrane potential. These results show a strong subtype specificity of the two PPAR subtypes alpha and gamma on lipid partitioning and insulin secretion when systematically compared in a beta-cell context.

PMID: 15878969 [PubMed - indexed for MEDLINE]

I have a headache from all this info-- and it's not from the herceptin
Carol

I have a headache from all this info-- and it's not from the herceptin
Carol

Hi Gina and others.
I have read all the posts with great interest. I especially was moved by your since of passing down your thoughts or wisdom, Gina. These ideas are certainly in the literature.
Tennyson:
" Far on the ringing plains of windy Troy.
I am a part of all that I have met;
Yet all experience is an arch wherethro’
Gleams that untravell’d world whose margin fades
For ever and forever when I move"
Best wishes,
Barbara H.

Sorry about repeating myself--- some kind of slip
Carol

This is going to sound crazy, but Gina's response bothered me for a LONG time and I couldn't figure out why.... After a lot more research, I think it finally hit me. So I went and found the topic again, and thought I would ask you guys.

I hope I don't offend Gina, she's a smart cookie! She has a long theory about Herceptin Ineffectiveness, and I was thinking:

1) Haven't the studies shown that MORE Herceptin gives the same results as the current dosages without increasing effectiveness?

2) Why not make the theory that the tumor cells have capabilities of "learning"? I used the term loosely though, because I don't think cancer cells are necessarily smart - but maybe just survive out of 'natural selection'.


Cancer isn't just one type of cell replicating itself over and over. It's a product of an immune system that fails to recognize a damaged cell. My left breast had er-/pr- grade 3, IDC. My right breast had er+/pr- moderately differentiated DCIS. When I found out about that, I was like how? How could I be er-/pr- in one breast and er+/pr- in the other? It wasn't about the cancer... It was about my immune systems inability to recognize bad cells. Our normal cells are constantly learning how to overcome viruses and all sorts of stuff. The immune system seems smart when it comes to foreign attack (in a lot of cases). But when it comes to our own body malfunction, it struggles - especially when our genetics aren't perfect.

We already know that cells have a LOT of receptors on their surface. HER2/neu is just one of them. But for those of us who are HER2+++, that's great right? Think about this made up example for a minute:

I would think Herceptin Ineffectiveness is a mechanism where those tumor cells (in their active state) whose cell surface makeup has a few more IGF-IR receptors, survive and replicate after Herceptin has blocked all of the HER2 receptors on its surface. Even though the HER2 receptors are plugged, the immune system doesn't necessarily kill the cell. For many of us, the chemotherapy is what goes in and kills all the fast dividing cells. Just because the receptors are blocked, doesn't mean the cell is dead.

Those cells that have almost all HER2 receptors are killed (while in their active state), because chemo comes in and recognizes it as a fast dividing cell. While on Herceptin alone, the stuff that's maybe got some IGF-IR receptors - could live (if not in their active state, maybe while in their inactive state. I am on the side of the fence of oncology theory that believe cancer cells 'hide' while in their stem cell slowly dividing state - which is why they evade chemotherapy). As those cells live, I think more are replicated with 'possibly' more of those type of IGF-IR receptors. As all the HER2 receptors start to disappear (because those cancer cells were killed - either because they had no receptors left or the chemo killed them) - we get cancer cells that continue to divide - even while taking Herceptin. <Maybe the HER2/neu receptors are being blocked, but the IGF-IR unblocked receptors allow the cell to survive and divide?>

Is it plausible?

<I used IGF-IR just because it's a hot topic and I can't remember all the other ones abbreviations>

I have been re-reading this thread and find it so interesting. I am not ER/PR- but the concept that declining hormone levels could feed the cancer...that is to say....somehow it helps to be young and pre-menstral just rang a little bell...lol. There is a actress from Threes Company would had breast cancer and has written books about and talks about increasing your hormone levels. Every time I hear references to her in this regard I sort of shake my head as it flying in the face of what I have been taught about breast cancer but perhaps she has some good ideas for you hormone negative gals??

Cathya

I just remembered her name.....Suzanne Summers.

Cathya