ANASTROZOLE+HERCEPTIN: possible justification

[heblaj01]

In reply to a previous post inquiring about the Herceptin activity on primary tumours (Effect Of Herceptin On Primary Tumour) the majority of responders implied that only chemo would cause regression (to allow less invasive surgical excision).
However one responder,Taffy, described an extraordinary quick & pronounced regression (from "orange to golf ball" size to use her terms).
She stated that in addition to newly prescribed Herceptin she was taking Anastrozole & fish oil pills (as well as occasional iron supplements). Her onc who was surprised by the sudden effectiveness of Herceptin stopped the previously prescribed chemo regimen.
This raised many questions about why Herceptin was so effective in her particular case. Is it a fortunate unexplainable single case or is there a plausible reason to suspect that either Anastrozole &/or fish oil pills may be additive to the effectiveness of Herceptin in a larger number of patients?

Some light on the possible effect of Anastrozole is shed by the comments in 2004 by Dr Kent Osborne (http://www.breastcancerupdate.com/bcu2004/4/osbourne.htm) were he stated (extracted):

Estrogen deprivation in HER2-positive, ER-positive breast cancer
As predicted based on model systems, estrogen deprivation has been shown to be beneficial in HER2-positive, ER-positive tumors. Even though such tumors have numerous estrogen receptors in the membrane and nucleus, and high growth factor signaling, if the estrogen receptors are not activated with a ligand such as tamoxifen or estrogen, neither of these pathways are activated.

A few years ago people doubted the results of Matt Ellis' study in which letrozole produced a much higher response rate than tamoxifen in patients with HER2-positive disease because the study involved a small number of patients. However, Mitch Dowsett's IMPACT trial has shown that another aromatase inhibitor — anastrozole — is also much better than tamoxifen in these patients. In practice, when HER2 is overexpressed, estrogen deprivation may be a better choice than tamoxifen — either an oophorectomy in younger women or an aromatase inhibitor in older women.

Tamoxifen resistance and the conversion of tumors from HER2-negative to HER2-positive

We have laboratory and clinical data suggesting that tamoxifen can convert a tumor from HER2-negative to HER2-positive (Figure 3.1). In an in vivo model using a cell line with low EGFR and HER2, we've shown that initially, tamoxifen has antiestrogenic activity on the tumor. However, after three or four months tamoxifen resistance develops, and tamoxifen acquires the ability to stimulate the tumor

It may be to evaluate the merits of combining Anastrozole & Herceptin that a clinical trial in Europe is underway as mentioned in the 2006 interview with Dr mark Pegram (http://www.medscape.com/viewarticle/520710 ):
Medscape: How important are the identified pathways, such as HER-2, in hormone receptor-positive patients?

Dr. Pegram: I think they are critical because of receptor cross-talk between receptor tyrosine kinases, such as HER-2, EGFR [epidermal growth factor receptor], or IGF [insulin-like growth factor] receptors. All of these have been implicated in the emergence of steroid hormone independence, and, if that is the case, then we need to exploit that receptor cross-talk pathophysiology and target it specifically. For example, letrozole plus or minus lapatinib is being studied in a large randomized phase 3 registrational trial. The study size is powered so that we will be able to critically evaluate even the HER-2-positive subset in this cohort. I see this as the first really serious effort to test this receptor tyrosine kinase steroid receptor cross-talk hypothesis in a pivotal clinical trial. There are other such randomized trials under way in Europe, for example, with anastrozole plus or minus trastuzumab. My understanding is that this study was almost presented this year at San Antonio, but they are several events shy of their first planned interim analysis. I am very anxious to see that study presented, perhaps at ASCO 2006. It is a small study, only about 100 patients per arm, so it is really more like a randomized phase 2. Therefore, I don't think it will be definitive, but it might give us some clues as to what to expect in the larger studies with similar designs.

Let's hope that the trial findings are going to be positive for the majority of patients.
In the meantime can we find out if there are other forum members who are taking Herceptin plus an aromatase inhibitor such as Letrozole, anastrozole etc..? With what results on primary & mets tumours?

[R.B.]

IF DHA and oestrogen are linked in a two way rather than oestrogen only effecting DHA... Taking higher levels of DHA may well push down oestogen.

Oestrogen and DHA are both central to fertility.

IS DHA one of several internal body marker regulators of oestrogen levels?

Thanks for the interesting post.

RB


RB



1: Am J Clin Nutr. 2004 Nov;80(5):1167-74. Related Articles, Links
Click here to read
Docosahexaenoic acid concentrations are higher in women than in men because of estrogenic effects.

Giltay EJ, Gooren LJ, Toorians AW, Katan MB, Zock PL.

Psychiatric Center GGZ Delfland, Delft, Netherlands. giltay@dds.nl

BACKGROUND: During pregnancy there is a high demand for docosahexaenoic acid (DHA), which is needed for formation of the fetal brain. Women who do not consume marine foods must synthesize DHA from fatty acid precursors in vegetable foods. OBJECTIVE: We studied sex differences in DHA status and the role of sex hormones. DESIGN: First, DHA status was compared between 72 male and 103 female healthy volunteers who ate the same rigidly controlled diets. Second, the effects of sex hormones were studied in 56 male-to-female transsexual subjects, who were treated with cyproterone acetate alone or randomly assigned to receive oral ethinyl estradiol or transdermal 17beta-estradiol combined with cyproterone acetate, and in 61 female-to-male transsexual subjects, who were treated with testosterone esters or randomly assigned for treatment with the aromatase inhibitor anastrozole or placebo in addition to the testosterone regimen. RESULTS: The proportion of DHA was 15 +/- 4% (x +/- SEM; P < 0.0005) higher in the women than in the men. Among the women, those taking oral contraceptives had 10 +/- 4% (P = 0.08) higher DHA concentrations than did those not taking oral contraceptives. Administration of oral ethinyl estradiol, but not transdermal 17beta-estradiol, increased DHA by 42 +/- 8% (P < 0.0005), whereas the antiandrogen cyproterone acetate did not affect DHA. Parenteral testosterone decreased DHA by 22 +/- 4% (P < 0.0005) in female-to-male transsexual subjects. Anastrozole decreased estradiol concentrations significantly and DHA concentrations nonsignificantly (9 +/- 6%; P = 0.09). CONCLUSION: Estrogens cause higher DHA concentrations in women than in men, probably by upregulating synthesis of DHA from vegetable precursors.

Publication Types:

* Clinical Trial
* Randomized Controlled Trial


PMID: 15531662 [PubMed - indexed for MEDLINE]

[ElaineM]

The combination of Anastrozole (Arimidex?)and Herceptin seems to be working for me.
Peace,
Elaine M
http://langetc.tripod.com/health11.html

[CLTann]

Are you also taking other chemo agents, as usually required in Herceptin infusion? I have heard no real cases where Herceptin is used without chemo.


Ann

I am on hercptin and just started letrosole having had my ovaries removed last month. I have been on 3 weekly herceptin infusions since the end of February. I had Ist Stage breast cancer positive to HER-2 , ES [9] and pr

Hi,
Sometimes I take Navelbine, but not every week.
Take care.
Elaine

[panicked911]

I just finished a year of herceptain w/out chemo and have been on arimidex for a year as well. I am told this is is going to become the standard treatment for stage 1 ers in the near future.
Susanne