Herceptin questions

[DianneS]

I am hoping that herceptin will work for me but a bit wary because there is no test to determine if it IS working or not.

So, how can the medical world say it 'works in about 50% of cases'? What is the determining factor? Getting a recurrence? Or something else?

There is a 39 page article/study done by Dr. Ralph Moss available free to look at online at his website. The article is called "Herceptin or Deceptin"? I'm bringing it to my doctor Tues. I see no reason to go onto Herceptin if what Dr. Moss says is true. He believes Herceptin is hyped and not the cure-all it is made up to be. I hope he's wrong.

I'd like to know what you guys think of this article.

I was told that Herceptin boosts my chances of no recurrence to 80% within 10 years but now I wonder what they base that figure upon. If women who are early breast stage were only given Herceptin in 2005 they don't have a 10 year span to even know what will happen 10 years from now. Prior to 2005 Herceptin was given only to stage IV breast cancer women. Please correct me if I'm wrong. I don't want to be a nay-sayer but I do want to know fact from fiction. Hope to get feedback from the article,
Diannes

[DianneS]

Thought it might help to have the link for the article that I mention above about Herceptin or Deceptin?:

http://www.cancerdecisions.com/121805_page.html

Diannes

[BonnieR]

I looked at the site. There are fees to read the articles.

[DianneS]

Yes there are. I got my article through a holistic practitioner but I would have paid the $9 to read what Dr. Moss has to say. Lots of people pay that much for a magazine. He also publishes for free Cancer Decisions that he will email you. I figure if it's about my health it's worth it.

You can also google Dr. Ralph Moss online and see what he's about.

I have some real questions to ask my doc about this drug, Herceptin, which only gives a 5.5% advantage to 'some patients' and the benefits do not outweigh the risks of heart damage/failure that occur in many patients.

There is no way presently (as a poster mentioned here) to measure if Herceptin is 'working' or not so how can they, in good faith, make these claims?

I think it gives a lot of false hope to people like myself, but then...when it comes to cancer it's easy to want to believe. I sure want to.

Diannes

[sassy]

Dianne,

There have been some previous discussions about this article on this forum in the past. If you go to the "Search" function and type in "Ralph Moss", you will find the previous threads.

[dlaxague]

Dianne, it's always good to ask questions and seek to understand. Unfortunately, many of the answers aren't there (yet).

The trials that produced the results that caused Herceptin to become standard adjuvant treatment for HER2+ disease are where most of the data comes from. Those trials began well before 2005 - that's when they were reported and standard care changed. I do not know how old the oldest data is but you are correct - there cannot be a lot of information about 10 year survival after adjuvant Herceptin.

So, how can the medical world say it 'works in about 50% of cases'?

In those adjuvant trials, women who received Herceptin in addition to their other treatment were 50% less likely to have a recurrence than those who received just "other treatment". Other treatment being surgery, chemo and where applicable, hormonal treatment.

As you say, there is no way to know if Herceptin is working for any one individual when it's used as adjuvant treatment. The same would be said of chemo and of hormonal treatment. No way to know if it's working. If you don't get a recurrence, something worked - surgery, chemo, Herceptin, and/or hormonal treatment. One of those things or some or all of them in concert. No way to know.

As for Ralph Moss, sometimes he makes some good points but I think that in this case he is just as guilty of manipulating the data as are the media reports that he accuses of doing the same. It's true that when reporting to a public that does not understand the difference between relative and absolute risk it's easy to make something sound much better (or worse) that it is. That's not Herceptin's fault.

It's true that Herceptin benefits only a small portion of breast cancer patients, but it never claimed differently. If we use the figure of 25% of all bc being HER2+ and then the figure of Herceptin working for 50% of those - that's only 12% of all breast cancer. But anything that offers a 50% reduction in recurrence is pretty amazing, to that subgroup that benefits from that reduction.

It seems like Ralph Moss is upset with the way that media reports health news, and is taking it out on Herceptin.
I don't know what he has to say about side effects. I don't think that there are any serious side effects showing up when an anthracycline chemo is not used with Herceptin. And I'm not willing to pay to read his words. His style of making dramatic statements that require me to pay to read the rest of the argument is annoying, and imho, decreases his credibility.

He has some valid points about conflict of interest among study investigators. His is an old article and doesn't mention another troubling issue r/t finances and personal financial interests, which is lack of further study about Herceptin's possible equal benefit when used over a much shorter duration.

But no matter how he nitpicks the reporting and the details and the financial gains involved - the fact remains that a 50% decrease in recurrence exists when Herceptin is used to treat HER2+ breast cancer.

Debbie Laxague

[madubois63]

I didn't read the article. $9 buys me almost 3 gallons of gas (as of yesterday). That will get me further than someones opinion.

I mentioned in another thread that I have been on Herceptin twice. I did not get Herceptin during my first bout with bc. I received Herceptin during my second bout with bc (mets to lung and liver). I took it with Carboplaten and Taxotere. The combo worked for me and killed off the bc within 9 months. Of course it may have been the chemo and not the Herceptin that worked , but I feel the Herceptin played a major factor in treating the bc. Unfortunately, Carboplaten induced acute myeloid leukemia in me. I had to stop all bc treatments, but I was in remission from the bc at that point anyway. I took a lot of chemo for the AML and then had a bone marrow transplant. After a year, the bc came back to my lung. I believe that if I had continued the Herceptin, it would not have come back. My beliefs are not fact and fact is what you are looking for. Since my 3rd bout with bc, I started Xeloda but had to stop - bad reaction. I now take only Herceptin and have for almost a year. PET/CAT scans show the tumors are half the size, so I know Herceptin is working for me. Be thankful that you don't have anything to scan.

I know your looking for answers. I've been there. If I listened to all the stats and percentages I'd have been dead a long time ago (and many times over). Now , the docs tell me this and that, I swallow the info, maybe cry a little, go home research it and then I make a choice. I know I no longer fit in to any category or any statistics. I am making my own stats.

I really hope the Herceptin is working for you and that you can be happy with the choice you've made.

[Lani]

Couple of studies in early breast cancer--many more studies in metastatic breast cancer (even one tied to AI efficacy prediction). Here are abstracts:

J BUON. 2008 Jul-Sep;13(3):409-13.

Extracellular domain of HER2: A useful marker for the initial workup and follow- up of HER2-positive breast cancer.
Garoufali A, Kyriakou F, Kountourakis P, Yioti I, Malliou S, Nikaki A, Kardara E, Frangos I, Koumna S, Baziotis N, Scorilas A, Ardavanis A.
Nuclear Medicine Laboratory, "St. Savvas" Anticancer Hospital, Athens, Greece.

Purpose: The extracellular domain (ECD) of the HER2 receptor is proposed as a real-time marker of HER2-positive breast cancer (BC). In this study, ECD-HER2 levels were compared with standard clinical and pathological prognostic factors. Patients and methods: In 247 consecutive patients (116 with early or localized BC, 116 with advanced or metastatic BC, and 16 with benign mastopathies), serum ECD-HER2 levels were measured. In 116 advanced-disease patients ECD-HER2 status was also studied by immunohistochemistry (IHC) and compared with established clinical and pathological variables. Results: Mean serum ECD-HER2 value was 19.62 ng/ml (median 10.35, range 3 - >250). Mean value in benign mastopathies was 9.04 ng/ml, 9.4 ng/ml in early disease and 34.5 ng/ml in advanced disease. No difference between benign mastopathies and early BC was observed, while significant difference between early and advanced BC (p<0.001) was noted. However, in advanced-disease patients a positive correlation of ECD-HER2 with IHC (p=0.002), disease grade (p=0.034) and level II axillary node involvement (p=0.011) was noted, as well as a significant negative correlation with estrogen receptor (ER) and progesterone receptor (PR) (p= 0.035 and p=0.011, respectively). Conclusion: ECD-HER2 is a reliable marker for breast cancer, as suggested from the existing literature; therefore, its integration in the initial workup and follow-up routine of breast cancer, particularly the HER2-positive, is proposed.

PMID: 18979558

: Ann Oncol. 2008 May;19(5):883-90. Epub 2008 Jan 10. Links

Evaluation of serum HER2 extracellular domain in early breast cancer patients: correlation with clinicopathological parameters and survival.
Ludovini V, Gori S, Colozza M, Pistola L, Rulli E, Floriani I, Pacifico E, Tofanetti FR, Sidoni A, Basurto C, Rulli A, Crinò L.
Medical Oncology Division, Azienda Ospedaliera of Perugia, Perugia, Italy. oncolab@hotmail.com

BACKGROUND: We explored the correlation between serum human epidermal growth factor receptor-2 (HER2) extracellular domain (ECD) and tissue HER2 status, their relationship with clinicopathological parameters and their impact on disease-free survival (DFS) and overall survival in early breast cancer patients. PATIENTS AND METHODS: This prospective trial included patients with stage I-III breast cancer. Serum HER2 ECD levels were measured by two enzyme-linked immunosorbent assays before surgical treatment. Tissue HER2 status was analyzed by immunohistochemistry (IHC) in all tumors; FISH assay was utilized in HER2 2+ tumors by IHC. RESULTS: From May 2000 to July 2005, 256 consecutive stage I-III breast cancer patients were included in this study. High serum HER2 ECD levels (>or=15 ng/ml) were reported in 23 patients (9.0%) and HER2-positive status in tumor tissue was observed in 42 patients (16.4%) with a concordance of 87.1%. High HER2 ECD levels were significantly associated with high histological grade (P = 0.003), stage III (P = 0.008), lymph node involvement (P = 0.035) and negativity of both estrogen (P = 0.016) and progesterone (P = 0.007) receptors. At multivariate analysis, high serum HER2 ECD levels were a significant independent prognostic factor of worse DFS (P = 0.009). CONCLUSIONS: A statistically significant association was observed between high serum HER2 ECD levels and worse DFS in early breast cancer patients.

PMID: 18187484
^^^^^^^^^^
Most other papers discuss changes in serum ECD in METASTATIC BC AND WHAT THEY say re whether herceptin will work:


Clinical utility of serum HER2/neu in monitoring and prediction of progression-free survival in metastatic breast cancer patients treated with trastuzumab-based therapies.

Esteva FJ, Cheli CD, Fritsche H, Fornier M, Slamon D, Thiel RP, Luftner D, Ghani F.
The University of Texas, MD Anderson Cancer Center, Houston, TX, USA. festeva@mdanderson.org
INTRODUCTION: The purpose of this retrospective study was to determine the clinical utility of serum HER2/neu in monitoring metastatic breast cancer patients undergoing trastuzumab-based therapy and to compare these results with those obtained using cancer antigen (CA) 15-3. We also sought to determine whether early changes in serum HER2/neu concentrations could be a predictor of progression-free survival. METHODS: Sera were obtained retrospectively from 103 women at four medical institutions. Patients eligible for participation were women with metastatic breast cancer who had HER2/neu tissue overexpression and were scheduled to be treated with trastuzumab with or without additional therapies as per the established practices of the treating physicians. A baseline serum sample for each patient was taken before trastuzumab-based therapy was started. Patients were subsequently monitored over 12 to 20 months and serum samples were taken at the time of clinical assessment and tested with Bayer's HER2/neu and CA15-3 assays. RESULTS: Concordance between clinical status in patients undergoing trastuzumab-based treatment and HER2/neu and CA15-3 used as single tests was 0.793 and 0.627, respectively, and increased to 0.829 when the tests were used in combination. Progression-free survival times did not differ significantly in patients with elevated baseline HER2/neu concentrations (> or = 15 ng/mL) and those with normal concentrations (<15 ng/mL). However, progression-free survival differed significantly (P = 0.043) according to whether the patient's HER2/neu concentration at 2 to 4 weeks after the start of therapy was >77% or < or = 77% of her baseline concentration. The median progression-free survival times for these two groups were 217 and 587 days, respectively. A similar trend was observed for a subcohort of patients treated specifically with a combination of trastuzumab and taxane. CONCLUSION: These findings indicate that serum HER2/neu testing is clinically valuable in monitoring metastatic breast cancer patients undergoing trastuzumab-based treatment and provides additional value over the commonly used CA15-3 test. The percentage of baseline HER2/neu concentrations in the early weeks after the start of therapy may be an early predictor of progression-free-survival.
PMID: 15987448




Breast Cancer Res Treat. 2008 Apr 25. [Epub ahead of print]

Changes over time of extracellular domain of HER2 (ECD/HER2) serum levels have prognostic value in metastatic breast cancer.
Bramwell VH, Doig GS, Tuck AB, Wilson SM, Tonkin KS, Tomiak A, Perera F, Vandenberg TA, Chambers AF.
London Regional Cancer Program, London, ON, Canada, vivienbr@cancerboard.ab.ca.

Background Blood levels of the extracellular domain of HER-2/neu (ECD/HER2) have been suggested to have potential as a tumor marker in breast cancer. Our aim was to assess the prognostic value of baseline levels of ECD/HER2, but more importantly changes in levels over time, in women with metastatic breast cancer. Methods Baseline and serial levels of ECD/HER2 were measured in 158 women with newly-diagnosed metastatic breast cancer, in whom we previously performed serial measurement of plasma osteopontin. ECD/HER2 was measured in 1,282 serum samples using a validated ELISA at baseline and every 3-12 weeks during and after therapy until death (median, n = 8 samples per patient). Multivariate time-dependent survival analyses were conducted using models that right-censored patient outcomes 3, 6 and 12 months after last known ECD/HER2 measurement. Results Thirty-four patients (22%) had elevated baseline ECD/HER2 (median 10.2 ng/ml: range 4.1-40.4 ng/ml). In univariate analysis, elevated baseline ECD/HER2 was associated with short survival (P = 0.001). In a multivariate model incorporating standard clinical prognostic factors, baseline ECD/HER2 was significantly associated with survival duration (RR 1.029; P = 0.020). Presence of visceral metastases and ECOG status 2-4 also retained significance. In a multivariate model incorporating standard prognostic factors and changes in sequential ECD/HER2 levels, an ECD/HER2 increase of >12 ng/ml at any time was the variable with most prognostic value for poor survival (RR 6.10; P = 0.0003); poor ECOG status also retained significance. Conclusion Increases over time of ECD/HER2 levels were strongly associated with poor survival in this cohort of women with metastatic breast cancer.

PMID: 18437556





Cancer. 2008 Jul 25. [Epub ahead of print]

Serum HER-2/neu and relative resistance to trastuzumab-based therapy in patients with metastatic breast cancer.
Ali SM, Carney WP, Esteva FJ, Fornier M, Harris L, Köstler WJ, Lotz JP, Luftner D, Pichon MF, Lipton A; the Serum HER‐2/neu Study Group.
Department of Hematology-Oncology, Penn State Hershey Cancer Center, Penn State University/Hershey Medical Center, Hershey, Pennsylvania.

BACKGROUND.: Previous reports based on small patient numbers suggested that changes in serum HER-2/neu levels may predict response or lack of response to trastuzumab-based therapies in metastatic breast cancer (MBC). The objectives of this study were to pool data from 307 patients with MBC from 7 medical institutions to validate that the serum HER-2/neu profile predicts patient resistance to trastuzumab and to establish a clinically relevant cutoff. METHODS.: This was an international, multicenter, retrospective analysis of individual pooled data from 307 patients with MBC who were treated with first-line trastuzumab-based therapy. Serum was collected at baseline and 30 to 120 days after the initiation of trastuzumab therapy. A serum HER-2/neu decrease >/=20% (receiver operating curve analysis) was defined as a significant HER-2/neu change. RESULTS.: Of the 307 patients with MBC, 191 patients (62%) had a significant decline (>20%) in serum HER-2/neu and 116 patients (38%) did not. The objective response rate was 57% for patients who achieved this decline in serum HER-2/neu (>20%) compared with 28% for patients who did not. Patients who achieved this decline in serum HER-2/neu also had a significantly longer time to disease progression (320 days vs 180 days; P < .0001), longer duration of response (369 days vs 230 days; P = .008), and longer overall survival (898 days vs 593 days; P < .018). CONCLUSIONS.: In this pooled analysis of 307 patients with MBC, individuals who did not achieve a significant decline (>/=20%) in serum HER-2/neu levels had decreased benefit from trastuzumab-based therapy, and these patients should be considered for clinical trials evaluating additional HER-2/neu-targeted interventions. Cancer 2008. (c) 2008 American Cancer Society.

Med Oncol. 2008 Oct 15. [Epub ahead of print] Links

Clinical significance and prognostic value of serum sHER-2/neu levels in patients with solid tumors.
Papila C, Uzun H, Balci H, Zerdali H, Sezgin C, Can G, Yanardag H.
Department of Internal Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey.

The purpose of this study was to determine HER-2/neu in the serum of patients with solid tumors and to investigate its potential usefulness in predicting the clinical course of the disease. At the same time, we compared the ability of serum HER-2/neu, CA15.3, CA12-5, CA19-9, carcino embryonic antigen (CEA), and alpha-feto-protein (AFP) in breast, colorectal, and lung cancer patients. Forty, thirty-six, and twenty-three patients with lung, colon and breast cancer were included in this study, respectively. Serum levels of HER-2/neu, CA15.3, CA12-5, CA19-9, CEA, and AFP were measured. Her-2 neu levels were significantly higher in the breast cancer groups than colorectal and lung cancer and controls groups (P < 0.01). There is no significant difference when compared with others groups (P > 0.05). There was a positive correlation between the HER-2/neu and CA15-3 values in breast cancer groups. We found 0.75(0.59-0.90) for Her-2/neu from the area under the curve (AUC). P-value for breast cancer is 0.003, and we discovered that 9 ng/ml was the best inersection point. In this situation, we calculated that sensitivity was 65.2%, specificity was 100%, positive predictive value was 100%, negative predictive value 75.8%, and accuracy was 83.4%. These findings indicate that serum HER2/neu levels are clinically valuable in monitoring metastatic breast cancer and non-small cell lung cancer patients. Prognosis of breast cancer provides an additional value over the commonly used CA15-3 test. Measurements of levels of serum HER-2/neu provide prognostic and predictive information to the clinician and can especially be used for monitoring metastatic breast cancer patients. Further clinical validation is needed to confirm these findings.

PMID: 18855148
^^^^^^^^^
and even one paper having to do with determining whether AIs efficacious in metastatic breast cancer

Cancer. 2007 Nov 15;110(10):2178-85. Links

High circulating HER2 extracellular domain levels correlate with reduced efficacy of an aromatase inhibitor in hormone receptor-positive metastatic breast cancer: a confirmatory prospective study.
Colomer R, Llombart-Cussac A, Lloveras B, Ramos M, Mayordomo JI, Fernández R, Tusquets I, Gil M, Barnadas A, Constenla M, Gilabert M, Alba E.
M. D. Anderson Cancer Center Spain, Madrid, Spain. rcolomer@seom.org

BACKGROUND: In this specifically designed, prospective study, the authors addressed the predictive value of circulating levels of the extracellular domain (ECD) of HER2 in patients with metastatic breast cancer who were treated with letrozole. METHODS: Two hundred twenty-six patients with hormone receptor-positive, metastatic breast cancer received letrozole (2.5 mg daily) until they developed either disease progression or unacceptable toxicity. Efficacy was measured primarily as the time to progression (TTP) and, secondarily, as the objective response rate (ORR) and overall survival. HER2 ECD levels were determined by using a sandwich enzyme HER2/neu immunoassay before letrozole treatment was initiated. Positive HER2 ECD status was correlated with treatment efficacy. RESULTS: Forty-two patients (19%) had elevated HER2 ECD levels, which were associated with primary tumor HER2 expression (P < .001) but not with age, performance status, location, or number of metastatic sites. The median TTP was significantly shorter among patients who had elevated HER2 ECD compared with the median TTP among patients who had normal levels (4 months vs 14 months; P = .0004), and the ORR was lower in the group with elevated HER2 ECD levels (14% vs 30%; P < .036). Overall survival was significantly shorter among patients with elevated serum HER-2 ECD (P < .0005). CONCLUSIONS: Elevated HER2 ECD concentrations predicted poorer outcomes in postmenopausal women with metastatic hormone receptor-positive breast cancer who were treated with aromatase inhibitors like letrozole. (c) 2007 American Cancer Society.

PMID: 17926331

[dlaxague]

serum her2 ECD if performed BEFORE&after surgery may help predict herceptin efficacy

Thanks for taking the time to post all those, Lani. But I don't understand how you drew the above conclusion. It sounds to me like serum HER2 ECD is basically just another tumor marker. Useful for following treatment of mets, and maybe giving information about treatment efficacy sooner than scans, but of little if any use adjuvantly. And I don't see anything at all about its ability to predict Herceptin efficacy in adjuvant disease. Did I skim too fast? Do you have time to explain?

Thanks for keeping us educated,
Debbie Laxague

[Lani]

From Dr. Slamon's paper's abstract--"A baseline serum sample for each patient was taken before trastuzumab-based therapy was started. Patients were subsequently monitored over 12 to 20 months and serum samples were taken at the time of clinical assessment and tested with Bayer's HER2/neu and CA15-3 assays" The abstract does not go into the detail that the paper does about retesting serumher2 about 3 weeks after the first dose--it is the~20% reduction at the second testing which according to the paper predicted herceptin efficacy. The patient's clinical course, ie, how well herceptin worked in them over the intervening 12-20 months was studied and came to the following conclusion--

CONCLUSION: These findings indicate that serum HER2/neu testing is clinically valuable in monitoring metastatic breast cancer patients undergoing trastuzumab-based treatment and provides additional value over the commonly used CA15-3 test. The percentage of baseline HER2/neu concentrations in the early weeks after the start of therapy may be an early predictor of progression-free-survival.

TO ME THAT MEANS IT IS A PREDICTOR OF HOW WELL HERCEPTIN MAY WORK, which may reflect both inherent efficacy ie, lack of inherent resistance. How much it reflects anything about the degree of acquired resisitance which may/may not occur and when it may occur is clearly debatable/unclear, but the bottom line is that those who achieved that degree in decrease in serum her2 ECD were those who responded the longest and had the longest progression free survival

Hope this helps

[freyja]

Dianne,
Hope your treatments are moving along, o.k. now. In regard to whether or not Herceptin will work for you, you've got a whole group of women and men here who wholeheartedly believe in it, and are living because of it. If your doctor finds that you are a candidate for it, and it MIGHT work, then why not try it? Just my opinion.
Celeste
(Maryanne you're my hero)

[dlaxague]

Lani said: TO ME THAT MEANS IT IS A PREDICTOR OF HOW WELL HERCEPTIN MAY WORK, which may reflect both inherent efficacy ie, lack of inherent resistance.

I didn't say there was no value to the test. It's a tumor marker, basically, and when a tumor marker accurately reflects amount of disease (which they do for some but not all breast cancer), they are useful to monitor metastatic disease and treatment of same. I hope that for HER2+ disease, they will be a more reliable tumor marker to help tailor treatment of metastatic disease.

However, I see nothing in the studies to support your original subject line about serum HER2 ECD testing before and after primary surgery being predictive of response to Herceptin. Yes, there's going to be a drop in serum HER2 ECD (if it was even elevated, which it isn't always) after surgery which removes the cancer (there had BETTER be a drop). But that doesn't tell us anything about Herceptin's efficacy.

There are studies of neoadjuvant Herceptin. If those used serum HER2 ECD, then we'd have some information, perhaps. But there are other ways to assess efficacy in that situation and serum HER2 ECD would have to show that it's easier, more accurate, or cheaper - which it may well be. I imagine that those studies are in progress.

I don't see that much on this list - neoadjuvant treatment. Who here has had neoadjuvant Herceptin?

I wish that there were something that could tell us, as Dianne wishes, that ADJUVANT treatment (all of it, not just Herceptin) is working but I do not think that we have that. Each time we find a more targeted treatment, like hormonal treatment, and Herceptin, and probably Tykerb, we get closer to knowing something is working. But we're not there yet.

Good discussion. Thanks, again, Lani - for taking the time. You are making a big difference to the lives of many people.

Debbie Laxague

[Lani]

http://www.news-medical.net/?id=43034

[dlaxague]

Maybe we're not communicating well here. I keep saying the same thing and you keep saying the same thing. Email is hard that way, sometimes.

I have no argument with the test for metastatic breast cancer. All the supporting evidence for this test is for use in metastatic disease, including the link that you just posted. Tumor markers and other ways to asses treatment response can be useful in the metatstatic setting, for those who choose to use them, and for whom they reflect disease status.

(I would, however, say that the test monitors rather than predicts, and that it is not Herceptin-specific. It should be equally useful for assessing response to chemo which is often given with Herceptin, and for Tykerb, too - right?)

But nothing I've seen says that it has any place in predicting or assessing Herceptin response before or after breast cancer surgery in the adjuvant setting. That's all I'm saying.

Your statement that "serum her2 ECD if performed BEFORE&after surgery may help predict herceptin efficacy", posted in response to someone who was asking how she could know if adjuvant Herceptin would work for her, has not been supported by any evidence that I've seen.

I feel like I'm being argumentative plus this is not a very important subject. But I do value accurate information and so am finding it hard to stop trying to clarify what we are telling Dianne, who is new and seeking truths.

Debbie Laxague

[gdpawel]

I've often wondered if the underlying science of Herceptin is sound. The benefits of the newer targeted therapies are marginal. These targeted therapies may impart a clinical benefit by stabilizing tumors, rather than shrinking them (substituting shrinkage for stabilization).

Targeted therapies need approaches to determine optimal dosing, to assess patient adherence to therapy, and to evaluate treatment effectiveness. To determine the dosing and effectiveness of targeted therapies, physicians are turning to pharmacodynamic end points, such as tumor metabolic activity on Pet Scans, levels of circulating tumor and endothelial cells (CTCs), and serial levels of target molecules in tumor tissue, adding more complexity, trying to identify the subset of patients most likely to benefit from specific drugs.

The molecular pathways most often targeted in the treatment of solid tumors are those of the epidermal growth factor receptor (EGFR, also known as HER1), vascular endothelial growth factor (VEGF), and HER2/neu (the Herceptin gene). Such pathways can be inhibited at multiple levels: by binding and neutralizing ligands (i.e., molecules that bind to specific receptor sites on cells); by occupying receptor-binding sites (thereby preventing ligand binding); by blocking receptor signaling within the cancer cell; or by interfering with downstream intracellular molecules.

Monoclonal antibodies, which are usually water soluble and large, target extracellular components of these pathways, such as ligands and receptor-binding domains. In contrast, small molecule inhibitors can enter cells, thereby blocking receptor signaling and interfering with downstream intracellular molecules.

What would be more beneficial is to test those pharmacodynamic endpoints with the ability to measure multiple parameters in cellular screens now in hand using flow cytometry. Using a systems biology approach where compounds are first screened in cell-based assays, with mechanistic understanding of the target coming only after validation of its impact on the biology.

Unlike a test for the presence of receptors to a specific antigen, which only "implies" dependence upon that antigen, a functional assay actually assesses the direct or indirect effect of the drug upon the whole cell, whether it is a tumor cell or an endothelial cell. Her2 just happens to be one molecule which has been implicated in the process but there may be more.

If it were the only protein involved, then one would expect that Her2 expression would correlate with Herceptin activity 100% of the time but it actually does so only about 20% of the time. The functional assay doesn't just focus on Her2 or any one protein or mechanism. Whether it's Her2 alone (unlikely) or in combination with other proteins and other mechanical factors, the assay works by assessing the net effect of all those factors.

Many of these drugs cry out for validated clinical biomarkers to help set dosage and select people likely to respond. And optimal and reproducible Her2 testing continues to evade the diagnositcs of the disease. Numerous other genes, tumor, and patient factors contribute to the risk of the cancer coming back and the effectiveness of chemotherapy for breast cancer.

It could be vastly more beneficial to measure the net effect of all processes (systems) instead of just individual molecular targets. The cell is a system, an integrated, interacting network of genes, proteins, and other cellular constituents that produce functions. One needs to analyze the systems' response to drug treatments, not just one or a few targets (pathways/mechanisms).

There are many pathways/mechanisms to the altered cellular (forest) function, hence all the different "trees" which correlate in different situations. Improvement can be made by measuring what happens at the end (the effects on the forest), rather than the status of the indivudal trees.