her2 and ER and PR status are age-related--triple positive bc occurs ~5 yrs earlier

[Lani]

Breast Cancer Res Treat. 2007 Aug 9; [Epub ahead of print]
Age interacts with the expression of steroid and HER-2 receptors in operable invasive breast cancer.

Neven P, Van Calster B, Van den Bempt I, Van Huffel S, Van Belle V, Hendrickx W, Decock J, Wildiers H, Paridaens R, Amant F, Leunen K, Berteloot P, Timmerman D, Van Limbergen E, Weltens C, Van den Bogaert W, Smeets A, Vergote I, Christiaens MR, Drijkoningen M.
Department of Obstetrics and Gynaecology, Multidisciplinary Breast Centre, University Hospitals Leuven, Herestraat 49, B-3000, Leuven, Belgium, Patrick.neven@uz.kuleuven.ac.be.
BACKGROUND: : The negative association between the oestrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER-2) in breast cancer travels in both directions. ER(+) tumours are less likely HER-2(+) and HER-2(+) tumours are less likely ER(+). METHODS: : We studied the age-related immunohistochemical (IHC) expression of ER, progesterone receptor (PR) and HER-2 in 2,227 tumours using age as a continuous variable. Steroid receptors were considered positive for any nuclear staining of invasive cancer cells and for HER-2, either for strong expression by IHC (score 3(+)) or gene amplification by fluorescence in situ hybridisation (FISH). Based on nonparametric regression, the age-related association between steroid receptors and HER-2 was presented as likelihood curves. RESULTS: : The association between ER or PR and HER-2 is age-related. The age-related expression of ER and PR is HER-2 dependent. In HER-2(-) cases, the odds ratio (OR) for being ER(+) was 2.594 (95% CI = 1.874-3.591) up to age 50 and age-independent thereafter; for PR-expression the OR was 2.687 (95% CI = 1.780-4.057) up to age 45 and 0.847 (95% CI = 0.761-0.942) thereafter. In HER-2(+) cases, the OR was 0.806 (95% CI = 0.656-0.991) to be ER(+) and 0.722 (95% CI = 0.589-0.886) to be PR(+). The age-related OR for breast cancers to be HER-2(+) is steroid receptor dependent. Taking together, ER(+)PR(+)HER-2(+) breast cancers appear on average 5.4 years earlier than breast cancers of any other ER/PR/HER-2 phenotype (95% CI = 3.3-7.5; P < 0.0001). CONCLUSION: : There is a qualitative interaction between age and expression of steroid and HER-2 receptors. Our findings suggest a strong age-related selective growth advantage for breast tumour cells belonging to the ER(+)PR(+)HER-2(+) subgroup.
PMID: 17687649 [PubMed - as supplied by publisher]

[Hopeful]

Lani,

Thank you VERY much for posting this abstract.

Hopeful

[hutchibk]

Normally I can sort of decipher these, but not this one. Can anyone put it in layman's terms for me?

[Margerie]

I think they are saying on average triple + bc is seen in younger women. 5 years younger than average age of other types bc.

Ding, ding, ding.... I am a winner. Triple + at 38 years young.

"Our findings suggest a strong age-related selective growth advantage for breast tumour cells belonging to the ER(+)PR(+)HER-2(+) subgroup."

Now what exactly is the growth advantage? I have always wondered if oral contraceptive use combined with delayed or no childbirth is an inconvenient combo.

[Lani]

there are various cells that become cancerous but those that are triple + win out in younger patients perhaps because of the hormonal enviroment or other external force which causes them to outgrow the others (think of weeds in a garden), perhaps because of other reasons. But I don't think they really know enough to be sure that is the model ie, that a potential tumor or tumor is made of of heterogeneous cells and which set wins out in the out-of-control growth game is determined by outside environment /hormonal environment/etc. is really operative.

Equally plausible is a stem cell theory where either the stem cell or any one(or several) of its pluripotential daughter cells has a certain set of characteristics--and it is the daughter cells which make up 99% OF THE tumor cells and which the pathologists look at, whereas the culprits, and the ones capable of causing recurrence after sitting dormant, are perhaps cells with a different set of ER,PR and her2 characteristics altogether.

Sorry to confuse you more!

[Becky]

Another way to look at it is at this very basic level (and this is VERY basic). When a cell divides, it reproduces its strands of DNA and then half goes to one cells and the other half goes to the other cell. Now, let’s say that half doesn’t go to one cell but one cell gets an extra strand (3 copies of a strand) – that means that the other cell only got one copy of that strand. Now, those 2 cells might be cancer precursors. Now those cells divide and since they are not “right” they may also not split up the strands of DNA evenly so now you have 2 differing lines of cells that are making mistakes (the line that has “more” and the line that has “less”). One line may preferentially take over because it is ER+ (in a younger premenopausal woman with plenty of estrogen). If the same thing happened in a perimenopausal woman, perhaps she would also have ER+ disease but it would only be 40% instead of 90% ER+ . The basic chemistry of the woman may come into play to predict the line that actually becomes the cancer or one or more of the lines may end up mutating so badly that they are not viable at all.<O:p</O:p
One must also consider that in all this, you may have a very dominant line and a very repressed line. Chemo or other treatments might knock out the dominant line and then the repressed line may rear its ugly head (might be a reason why cancer “changes” and becomes ER+ when it was once ER- etc). Just some food for thought on this interesting research work done in this study.

Also, not to be forgotten is that what kind of cell in the duct or lobe can predict pathology (inside lining of the duct, more internal or the outside cells (ie: basal cells aka triple negative cancers)<O:p</O:p

[Hopeful]

Understanding their findings is compounded because the article was either written (or translated into) English by someone for whom English is not the native language.

The authors sought to expand on earlier work detailed in a paper (which was an easier read!) where they determined that the ER+/PR- HER2+ phenotype was age dependant and was strongly associated with middle age. That study was questioned because of the small numbers of patients involved, so they sought to do a larger study with more patients.

What they found in the study population was that triple positives (ER+/PR+/Her2+) are the only group where the likelihood of Her2 positivity declines with age, i.e., the older you are and ER+/PR+, the less likely you are to be Her2+. Other Her2+ partially hormone positive phenotypes (ER-/PR+ or ER+/PR-) showed a constant probability that was not age related.

They consider their work hypothesis generating and not conclusive. Their theory is that hormone positive, Her2+ bc in younger women is regulated more by endocrines than growth factor signaling, and that these tumors are more sensitive to endocrine maniputlation, and that menopausal tumors that are hormone positive and Her2+ are more endocrine independent and less responsive to endocrine therapy. The reasoning this is based upon is the higher levels of circulating estrongen in the bloodstream of pre-meno women. They stress that testing must be done to prove or disprove this theory. If this turns out to be accurate, I think it is also a statement about the difference between ER+ bc driven by estrogen and ER+ bc driven by aromatase, which seems trickier to control with estrogen manipulation in the Her2+ context.

The issue I have is how they define "young". I thought the "young" vs. "old" categories referred to pre and post menopause, but then they say, "In conclusion, our believe that HER-2 expression is estrogen driven in young women with an ER<SUP>+</SUP> breast cancers is reflected by a mean younger age of diagnosis (52.4 years) of ER<SUP>+</SUP>PR<SUP>+</SUP>HER-2<SUP>+</SUP> breast cancers, on average 5.4 years younger than lesions with another ER/PR/HER-2 receptor status (95% CI = 3.3–7.5; P < 0.0001)."

Again, my math skills aren't my strong suit, but I am guessing this means that the larger number of pre-meno triple positives offsets the much lower number of post-meno triple positives and thus brings down the mean age for the entire group to where it is lower than that of any other phenotype.

Hope this helps.

Hopeful

[Adriana Mangus]

Dear Margie:

I was too dx at 38 y/o, foward to 2003 and the cancer has mutated, now am ER,PR negative. Dx. with mets to rt lung, sternum July 16, 2003.

When I asked the onc, that's the simple explanation I was provided with...
"your cancer has mutated" I was post-menopausal at the time of recurrence, young @ menopause, due to chemo drugs.

I really do not know what to believe....?

[Hopeful]

Margerie,

I am in the group of women who used oral contraceptives for a long time and am childless. I question its relationship to my bc, also.

Hopeful

[dskdrive]

I used Birth Control Pills for probably 30 years and did not have a child until mid 30's. I am ER and PR strongly positive and HER2+++. Diagnosed at age 50 in 2004.