PTEN positive

[michele u]

I got my lab back from Targeted Molecular Diagnostics. My PTEN was positive. That's good. All of the info i've read is that if you have PTEN the Herceptin should work.My EGFR came back 1+. It looks like they read it out like Her2, 1+ 2+ and 3+ I wanted that one negative. It sounds like if it is positive, then that's just one more pathway the cancer can find to grow again. It's only 1+ so i don't if that is good or bad? What are your thoughts on the EGFR?

[al from Canada]

Sorry for taking so long but we have not forgotten about you but this a very conplex thing and will get even more complex as we add other mokecular targets to our profiling abd try to match these up with other downstream interactions and the appropriate targetted therapies. This topic is also very close to where my personal theories on ERGF X-talk / PI3K / PTEN / Insulin resistance / heat hock proteins / VEGF interactions relate to putting the brakes on the proliferation of this horrible disease. There is no magic bullet that will ever be found as a curative measure because clearly, there are too many pathways, escape mechanisms and individual differences that impact the the outcome of any one's therapy. There are common factors within HER2 cancers that offer a glimmer of hope and treatment combinations that haven't been explored.
I believe one route, and I've been hammering away at this of months now, is the use of Hercpetin + a variety of HER1 inhibitors + other tagetted therapies that have a compounded effect on blocking / activating other related pathways to cancer proliferation.

Here is one and altough it refers to prostate Ca, there are undeniable similarities with BC.

C Festuccia1, P Muzi1, D Millimaggi1, L Biordi1, G L Gravina2, S Speca1, A Angelucci2, V Dolo1, C Vicentini2 and M Bologna1,3


1 Departments of Experimental Medicine,
2 Surgery and
3 Basic and Applied Biology, University of L’Aquila, Via Vetoio, Coppito-2, 67100 L’Aquila, Italy


(Requests for offprints should be addressed to C Festuccia; Email: festucci@univaq.it ) To date, no effective therapeutic treatment allows abrogation of the progression of prostate cancer (PCa) to more invasive forms. One of the major targets for the therapy in PCa can be epidermal growth factor receptor (EGFR), which signals via the phosphoinositide 3'-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) pathways, among others. Despite multiple reports of overexpression in PCa, the reliance on activated EGFR and its downstream signalling to the PI3K and/or MAPK/extracellular signal-regulated kinase (ERK) pathways has not been fully elucidated. We reported that the EGFR-selective tyrosine kinase inhibitor gefitinib (ZD1839; Iressa) is able to induce growth inhibition, G1 arrest and apoptosis in PCa cells and that its effectiveness is associated primarily with phosphatase and tensin homologue deleted from chromosome 10 (PTEN) expression (and thus Akt activity). In fact PTEN-negative PCa cells are slowly sensitive to gefitinib treatment, because this molecule is unable to downregulate PI3K/Akt activity. PI3K inhibition, by LY294002 or after PTEN transfection, restores EGFR-stimulated Akt signalling and sensitizes the cells to pro-apoptotic action of gefitinib. The MAPK pathway seems to be involved primarily on cell-growth modulation because dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition (both not cell apoptosis) in PTEN-positive PCa cells and reduced EGF-mediated growth in PTEN-negative cells. Thus the effectiveness of gefitinib requires growth factor receptor-stimulated PI3K/Akt and MAPK signalling to be intact and functional. The loss of the PTEN activity leads to uncoupling of this signalling pathway, determining a partial gefitinib resistance. Moreover, gefitinib sensitivity may be maintained in these cells through its inhibitory potential in MAPK/ERK pathway activity, modulating proliferative EGFR-triggered events. Therefore, our data suggest that the inhibition of EGFR signalling can result in a significant growth reduction and in increased apoptosis in EGFR-overexpressing PCa cells with different modalities, which are regulated by PTEN status, and this may have relevance in the clinical setting of PCa.

In this article, PTEN is also associated with VEGF and what is also interesting is that the % of PTEN loss is the same as HER2 overexpression.

Loss of PTEN expression has been associated with advanced stages of tumor. Tumor angiogenesis is involved in tumor progression. In breast cancer, a high frequency of mutations of the PTEN locus has been reported. However, the prognostic importance of PTEN expression and its correlation with angiogenesis in breast cancer have not been well established. Formalin-fixed, paraffin-embedded tissues from 99 women with a primary diagnosis of invasive ductal carcinoma were evaluated for PTEN expression by immunohistochemical methods. The microvessel density (MVD) was also studied by immunohistochemical labeling of endothelial cells with CD34 antibody. Computerized image analysis was used to evaluate MVD. Reduced PTEN expression was seen in 27.3% of invasive ductal carcinoma. The MVD ranged from 22.0 to 197.0, with a median value of 58.5 (65.4 +/- 27.9). Reduced PTEN expression correlated with lymph node status (P < 0.01), tumor grade (P < 0.05), and tumor-node-metastasis (TNM) stage (P < 0.05). There was a statistically significant correlation between reduced PTEN expression and increased MVD (P < 0.05). The mean MVD was higher in reduced PTEN-expressive tumors, irrespective of stage, compared with normal PTEN-expressive tumors with the same stage. On multivariate analysis, only TNM stage and reduced PTEN expression correlated with survival. Our results suggest that reduced PTEN expression may be an independent prognostic indicator in patients with invasive ductal carcinoma. PTEN loss may be associated with increased tumor angiogenesis.

There is much more on this and many other complicating factors but you have to start somewhere.

Take care,
Al

[al from Canada]

Again in prostate cancer but what is interesting here is that EGFR (ERB1) has more of an impact on mets than HER2 in fact, 100% of mets were EGFR!
Still not forgetting that PCa is not BCa but it is the closest cousin.
Al

Expression of Epidermal Growth Factor Receptor Correlates with Disease Relapse and Progression to Androgen-independence in Human Prostate Cancer1

Giuseppe Di Lorenzo, Giampaolo Tortora, Francesco P. D’Armiento, Gaetano De Rosa, Stefania Staibano, Riccardo Autorino, Massimo D’Armiento, Michele De Laurentiis, Sabino De Placido, Giuseppe Catalano, A. Raffaele Bianco and Fortunato Ciardiello2


Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica [G. D. L., G. T., M. D. L., S. D. P., A. R. B., F. C.] and Dipartimento di Scienze Biomorfologiche e Funzionali [F. P. D. A., G. D. R., S. S.], UniversitÃ* degli Studi di Napoli Federico II, 80131 Naples, and Clinica Urologica [R. A., M. D. A.] and Cattedra di Oncologia Medica, Dipartimento di Medicina Sperimentale [G. C.], Seconda UniversitÃ* degli Studi di Napoli, Naples, Italy




Purpose: The transforming growth factor -epidermal growth factor receptor (EGFR) autocrine pathway has been implicated in prostate cancer cell growth. Amplification and/or overexpression of c-erbB-2, a receptor closely related to the EGFR, has been recently involved in prostate cancer progression. We investigated EGFR and c-erbB-2 expression in primary androgen-dependent and in advanced androgen-independent prostate cancer and their potential role as markers of disease progression.

Experimental Design: EGFR and c-erbB-2 expression were evaluated by immunohistochemistry in a consecutive series of 74 prostate cancer patients with the following characteristics: 29 patients (group 1) treated with radical prostatectomy; 29 patients (group 2) treated with luteinizing hormone-releasing hormone analogues and antiandrogen therapy followed by radical prostatectomy; and 16 patients with hormone-refractory metastatic disease. In all patients we evaluated: association between EGFR and/or c-erbB-2 expression and clinicopathological parameters; and disease-free survival according to EGFR and c-erbB-2 expression in univariate analysis (Kaplan-Meier product-limit method) and in multivariate analysis (Cox proportional hazards regression model).

Results: EGFR expression was found in 12 of 29 (41.4%) group 1 patients, in 22 of 29 (75.9%) group 2 patients (P < 0.0005), and in 16 of 16 (100%) metastatic patients (P < 0.005), whereas c-erbB-2 expression was found in 11 of 29 (37.9%) group 1, in 10 of 29 (34.5%) group 2 patients, and in 9 of 16 (56.3%) metastatic patients. A significant association was found between EGFR expression and a high Gleason score (P < 0.01) and between EGFR expression and higher serum prostate-specific antigen values (P < 0.02) in all groups of patients. Among the 58 patients treated with radical prostatectomy, 23 of 34 EGFR-positive patients (67.6%) relapsed, whereas only 2 of 24 EGFR-negative patients (8.3%) relapsed (P < 0.00004). c-erbB-2 expression did not significantly correlate with disease relapse (P = 0.07). In a Cox multivariate analysis, the only parameter with an independent prognostic effect on disease-free survival was EGFR expression (relative hazard, 11.23; P = 0.0014). Conclusions: EGFR expression increases during the natural history of prostate cancer. Correlation with disease progression and hormone-refractory disease suggests that EGFR-targeted drugs could be of therapeutic relevance in prostate cancer\

[Esther]

Can I just ask for a PTEN test? Or is this a specialized test that only the one lab can do?

[Lisa]

Can someone explain to my pea brain in simple terms what this is?


Love and light,

Lisa

[Helen]

I tried to read Al's and it went over my head. Can i ask a dumb question? Why do we want PTEN and EGFR tested? Do we ask our onc's for these type of test for lab requisition? What do we do with the results? Will our onc's act on it?
Thanks.

Helen

PTEN is a biomarker like Her2 is. In trials they think that you need PTEN to be present for Herceptin to respond. But, if you dont have it, they are just in trials to get PTEN inhibitors. This might be years down the road. EGFR is a biomarker too. They found if Her2 is stopped then the cancer might find it's way through the EGFR pathway if you have that present. EGFR inhibitors are like Lapatinib which is in trials right now. Michele u

[aquinis2000]

I like the other ladies are just starting to understand this pten and egfr stuff. i guess i really would rather have a "wait and see " attitude about the pten biomarker. because i really don't want to know if i don't have it. denial, denial, denial. thats been the only to get thru this sometimes. if i think i have it , maybe i can just go get my herceptin with a "this is going to whip this cancer" attitude. instead of going to get it knowing it is probably not working. i understand that if its not working, you could probably get into a trial of something else, but i would like to keep getting it with a good attitude, untill some ct scan or symptom tells me differently. just my demented opinion

I agree with you as to the potential complexity and "individual" nature of cancer due to the mass of factors. The more one reads the more complex it evidently all is.

This all brings me back to thinking that a variable that can be controlled and is repeated reported to have impact, in at least some instances, is diet. No it will not change genetic predisposition etc, but even there may have some mitigating impact.

Balancing omega threes and sixes, inclusion of greens high coulored veg, pulses to help elimination low salt and keep overall fats down with the jury out on dairy (re calcium absorbtion, and possible hormones and growth factors in dairy v CLAs etc) seem to common themes in may books on a wide range of medical conditions. Plants are veritable pharmacies which our bodies have evolved to use over very long time frames. Fats are often repored as an evolutionary factor, acting as hormones, and trials have shown the very significantly change gene experession based on type. (It takes time for the body to adapt, at least three months for example to see a change in breast tissue fats.)

Clearly some gentic factors will not be amenable to diet, and there are no guarantees but it comes with limited side effects, and provides the body with an immensly comlex and rich mix of natures pharaceuticals, and is the fuel the body has grown to need (probably the more diverse the better).

I "forced" myself to watch a TV series on human disection, which I expected to make me cringe, but instead in an odd way I was fascinated. How for example did this visually inellegant amorphous unprepossessing set of internal plumbing maintain itself and convert food into energy and all the body needs to maintain itself. A sense of wonderment set in, combined with a sense of the arrogance of man if we were in any way suggesting we have really got to grips with the complexity of it all, or were doing much more than poking at it with a sharp stick (a very significant step from a sledge hammer) to see what happened, and if it was something vaguely benificial regarding it as a treatment. For clarification I am not referring to treatment of microorganisms, viruses, or the impact of external factors where huge medical progess has been made, but the bodies own internal process which is what is being "mechaniced with" in cancer.

And from this came an unformed conclusion that as a start we really should be doing our best to ensure that this immensly complex organism (us) generally got what it needed and had adapted to over a very long time in food terms, and that we were being unreasonable if we expected something as comlex as us, which was used to generally running a a very wide variety of top quality fuel (with some reserve capacity), to run on crude or heavly adulterated fuel, or a predominace of things it has not seen before.


RB

[al from Canada]

My apologies ladies for unwittingly complicating this for many of you. I think the intent of my post(s) was to bring an awareness that as our treatments may become more complex (and targetted) and so will the molecular profiling. When I think back on one of the very first discussions on this board about this very topic, it was about oleaic acid (omega 9's in olive oil) and synergy with herceptin.

What we've learned since then is that blocking one pathway (say HER2) is a short fix (for most) and blocking more that one pathway (such as EGFR or VGEF or ER with iressa or avastin or arimidex respectively) may lead to a more sustained response.

As far as being prositive or negative...the jury is still out. For example, HER2 positive has turned into what no one would have predicted.... a blessing in disguise. Only time will tell about the rest.

As always,
Al

[michele u]

Al, your so right about the "blessing in disguise". I remember reading my path report. It read "Her2 positive---UNFAVORABLE" Now look what it's come to! Herceptin might have saved my life and they told me UNFAVORABLE. Looks like we all showed them---huh!!!

[lu ann]

When I was first dx. with recurrance I went to see my origional rad. onc. He was to give me rad. tx. after my lumpectomy 14 1/2 years ago. I never had a lumpectomy because my breast surgeon could not get clean margins. Anyway, I remember my rad. onc. saying "if you were going to have an aggressive cancer, her2 was the best kind to have". At the time I thought I only had 6 months to live. That was 2 years ago. I havn't been able to manage this disease with herceptin alone, but have had stable disease using a combination of drugs. Blessings. Lu Ann.

[Gina]

From the very beginning of my liver mets, it was noted that my tumors were extremely positive for EGFR and her-2, FYI.

Interesting that 16 out of 16 prostate cancer mets folks were also positive for EGFR.

Thanks for posting.

Gina

[Sammy]

Michelle, can u please tell me how and where you got PTEN test done ? I am very new to this site and very scared. Please guide me.

[heblaj01]

Gina,

Your case is always full of unexpected & seemingly conflicting conditions which are resolving themselves fortunately into favorable outcomes.
Are you the one in a million lucky one?
Or is there something to be learned from your travails that might be usefull to others?
I am referring first to your statement in the above post in this thread that you were initially found to be highly positive for both EGFR & HER.
Second, this not only did not make you resistant to Herceptin (as a single drug treatment) but even let you stop & start 4 times the treatment, each time succeeding in regressing liver mets over about 4 years!

I know you attribute the regressions to the higher than normal number of heavy loading doses . But how do you explain the absence of resistance in the face of high EFGR?

Were EFGR & HER levels checked only once? Could they be changing over time?
Any personal opinion or comment from your onc?