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]

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]

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

[Julie2]

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

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

[al from Canada]

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

[al from Canada]

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

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?

[al from Canada]

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

[Shell]

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?

[RobinP]

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.

[Gina]

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

[Becky]

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

[RobinP]

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.

[Julie2]

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

[RobinP]

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.

[Becky]

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

[RobinP]

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.

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