here we go again: How inexact ER status testing is!!!

[Lani]

: Am J Clin Pathol. 2007 Mar;127(3):356-65. Links
Comparison of evaluations for hormone receptors in breast carcinoma using two manual and three automated immunohistochemical assays.

Arihiro K, Umemura S, Kurosumi M, Moriya T, Oyama T, Yamashita H, Umekita Y, Komoike Y, Shimizu C, Fukushima H, Kajiwara H, Akiyama F.
Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan.
The aims of this study were to compare the quality of immunohistochemical assays of estrogen receptor (ER) and progesterone receptor (PR) and to compare the intermethod variability of assays from different manufacturers. immunohistochemical staining was entrusted to the following laboratories in Japan: Kyowa Medex, dealing with the products of BioGenex (Mishima, Shizuoka), DAKO Japan (Kyoto) and Ventana Japan (Yokohama). All slides were semiquantitatively evaluated according to the Allred score. Intermethod variability showed fair to moderate multirater kappa values for ER and PR (for total score, ER, kappa = 0.34; PR, kappa = 0.45). Another scoring system was also applied in which, irrespective of the intensity of nuclear staining, the proportion of cells stained in each specimen was recorded as 0; less than 1%; 1% or more and less than 10%; or 10% or more. Intermethod variability showed substantial multirater kappa values for ER and PR (according to percentage of positive cells, ER, kappa = 0.67; PR, kappa = 0.72). Concerning intermethod consistency, the scoring system based on the percentage of positive cells was advantageous over other scoring systems.
PMID: 17276950 [PubMed - indexed for MEDLINE]


Related Links
Quality assurance for detection of estrogen and progesterone receptors by immunohistochemistry in Austrian pathology laboratories. [Virchows Arch. 2002]
The effects of fixation, processing and evaluation criteria on immunohistochemical detection of hormone receptors in breast cancer. [Breast Cancer. 2007]
Interobserver reproducibility of immunocytochemical estrogen- and progesterone receptor status assessment in breast cancer. [Anticancer Res. 1996]
Immunohistochemical demonstration of oestrogen and progesterone receptors: correlation of standards achieved on in house tumours with that achieved on external quality assessment material in over 150 laboratories from 26 countries. [J Clin Pathol. 2000]
Simultaneous immunohistochemical and biochemical hormone receptor assessment in breast cancer provides complementary prognostic information. [Anticancer Res. 1997]
See all Related Articles...

[Lani]

Rhodes A, Jasani B, Balaton AJ, Miller KD.
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Immunohistochemical demonstration of oestrogen and progesterone receptors: correlation of standards achieved on in house tumours with that achieved on external quality assessment material in over 150 laboratories from 26 countries.
J Clin Pathol. 2000 Apr;53(4):292-301.
PMID: 10823126 [PubMed - indexed for MEDLINE]
6:
Biesterfeld S, Schroder W, Steinhagen G, Koch R, Veuskens U, Schmitz FJ, Handt S, Bocking A.
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Simultaneous immunohistochemical and biochemical hormone receptor assessment in breast cancer provides complementary prognostic information.
Anticancer Res. 1997 Nov-Dec;17(6D):4723-9.
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7:
Ogawa Y, Moriya T, Kato Y, Oguma M, Ikeda K, Takashima T, Nakata B, Ishikawa T, Hirakawa K.
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Immunohistochemical assessment for estrogen receptor and progesterone receptor status in breast cancer: analysis for a cut-off point as the predictor for endocrine therapy.
Breast Cancer. 2004;11(3):267-75.
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8:
Fisher ER, Anderson S, Dean S, Dabbs D, Fisher B, Siderits R, Pritchard J, Pereira T, Geyer C, Wolmark N.
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Solving the dilemma of the immunohistochemical and other methods used for scoring estrogen receptor and progesterone receptor in patients with invasive breast carcinoma.
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Helin HJ, Helle MJ, Helin ML, Isola JJ.
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Krishnamurthy S, Dimashkieh H, Patel S, Sneige N.
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Nichols GE, Frierson HF Jr, Boyd JC, Hanigan MH.
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Automated immunohistochemical assay for estrogen receptor status in breast cancer using monoclonal antibody CC4-5 on the Ventana ES.
Am J Clin Pathol. 1996 Sep;106(3):332-8.
PMID: 8816590 [PubMed - indexed for MEDLINE]
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Tabbara SO, Sidawy MK, Frost AR, Brosky KR, Coles V, Hecht S, Radcliffe G, Sherman ME.
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The stability of estrogen and progesterone receptor expression on breast carcinoma cells stored as PreservCyt suspensions and as ThinPrep slides.
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PMID: 9915137 [PubMed - indexed for MEDLINE]
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Wilbur DC, Willis J, Mooney RA, Fallon MA, Moynes R, di Sant'Agnese PA.
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Estrogen and progesterone receptor detection in archival formalin-fixed, paraffin-embedded tissue from breast carcinoma: a comparison of immunohistochemistry with the dextran-coated charcoal assay.
Mod Pathol. 1992 Jan;5(1):79-84.
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Maiorana A, Cavallari V, Bagni A, Ussia F, Maiorana MC, Fano RA.
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Anal Cell Pathol. 1996 Aug;11(3):199-209.
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Chebil G, Bendahl PO, Ferno M; South Sweden Breast Cancer Group; North Sweden Breast Cancer Group.
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Golouh R, Vrhovec I, Bracko M, Frkovic-Grazio S.
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Biesterfeld S, Kraus HL, Reineke T, Muys L, Mihalcea AM, Rudlowski C.
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Keshgegian AA.
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Nadji M, Gomez-Fernandez C, Ganjei-Azar P, Morales AR.
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Leers MP, Hoop JG, van Beers M, van Rodijnen N, Pannebakker M, Nap M.
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[Hopeful]

Lani, you are amazing! Thanks so much.

Hopeful

[SoCalGal]

Hi Lani,
Based upon feedback from this site, I asked my onc yesterday if we shouldn't do a biopsy (maybe from lung mets) to see what this cancer is. I asked if er/pr negative can "turn" positive - he said NO. I asked if her2+++ can turn negative - he said NO. The last time they removed something from me, it was the fall of 2005, a local tiny recurrance right at scarline.

He said he "knew" what my cancer was and there was absolutely no reason to do a biopsy. He said a lung mets biopsy wouldn't tell him about the other areas.

Sigh...after reading your posts it's hard not to wonder and worry.

BTW, what is your DX and treatment?

Thanks for all this valuable info. Blessings.
Flori

[TSund]

I think I may have posted these elsewhere but haven't received opinions yet:

1) Is it possible that ER+/HER2+ tumors "need" chemo or react to chemo differently than ER+ alone? I ask this because Ruth is 100% ER+/95% PR+ and so far has had a pretty dramatic response to pre-adjuvant TCH chemo.

2) Since Herceptin has been shown to work better with chemo is there some synergistic work between the two which indicates it either way for HER2+ or does that bring us again back to 1) above?

3) Would this data on ER+ testing mostly affect those who are ER-? (in the idea that they might need the hormone treament after all if test was in accurate) Would it possibly affect treatment regime decisions on those who are showing ER+?

4) Lani, can you translate this into a recommendation? When Ruth has her surgery and sentinel node biopsy should we ask for a different dye or since she's already established ER+ is it not a big deal? Can the dye affect anything else?

Lani, Your research is ALWaYS very interesting..tho hard for me to slog thru! I always appreciate it when you put a few words in to translate!

[Lani]

1) they have found that ER+PR+ react differently to antihormonals than ER+PR-. Hormonallly positive tumors receive much less benefit (if any from Chemo) her2+ER+ may be the exception, but it may not be all of them eg it may be those which are topoIIa + and respond to anthracyclines. It SEEMS her2+ER+ respond to taxanes, whether more or les than ER- is not known. It won't probably be known until they discover how to subclassify the different types of her2+ER+ bc and find which respond best to what treatment.
Ruth's dramatic response portends well!!!

2) did n't understand the question. Sorry!

3) If one is ER- and they miss it, treatment may not include antihormonals which may improve prognosis. If one is falsely diagnosed as ER+, perhaps one decided to forgo chemo thinking the benefit would be small and/or one would be treated with a drug which may have unnecessary side-effects

4) Don't know if the dye can affect anything else. Search for my post on the methylene blue and print it out. Other dyes were used in Europe, but cost more and may not be available to the surgeon here. I just read a paper showing that using the radioactive material alone can miss some metastatic deposits in sentinel nodes, hence the recommendation to use both.

If Ruth was ER+ when methylene blue was not used, the same tissue could be reexamined using another technique to reconfirm the ER positivity. A
pathologist at a breast cancer conference I attended two weekends ago brought up in front of all of his colleagues and oncologists that it is time to reexamine how ER is tested for as better, more reliable methods are available and/or testing in more than one way to assure the results are accurate may be in order.


I am certainly not an oncologist, pathologist, or breast surgeon or in any way qualified to advise you...just well-read.

If anyone is truly concerned, print out some of the articles or abstracts and take it with you when you ask questions. There are such things as pathologic second opinions where you don't even have to go, just send your slides. No
point in worrying unless it will change your treatment . One member of the board had tested initially ER+ on the needle biopsy, then ER- when the tumor was removed. Perhaps in that sort of instance suspicions might be raised. Remember mistakes are the exception, not the rule. But asking questions is part of the process...

Hope this helped more than raised worries!

[Lani]

gotta go (long post for TSUND) so will make this fast

her2+ virtually always metastasizes at her2+ (can cite papers if needed)
Usually if discordant, method of her2 testing reexamined

At conferences I attend, including SABCS, the oncologists are always bemoaning the fact that they don't get a chance to get a biopsy of mets
(I raised my hand and asked why bone marrow biopsies aren't more prevalent to assess residual disease and was either ignored or scoffed at)

Lung mets can be dangerous to biopsy and sometimes very inaccessible.

ER negatives usually don't "turn positive" but giving lapatinib can cause a 40-70% increase in ERs I believe I read--so if you were .8% positive (considered negative) I suppose you could become positive.It isn't that the ER- tumors "turn" positive, it is that they were misdiagnosed for technical reasons initially or perhaps that a treatment allowed those cells which had ERs to be selected out (like weeds in a garden, if you use a weed killer that doesn't get dandelions, dandelions will no longer have to compete with the other weeds and will become predominant.

Walter Carney has published on the use of serum her2 to detect those tumors which start out her2- but become her2+ when they become resistant to antihormonals and/or recur.

Most answers in cancer are not "yes" and "no". It is far to complicated a field and too poorly understood. Let's hope it doesn't stay that way long!

[Bronny]

After surgery, 18 months ago I was told I was hormone negative, HER2 + so my treatment included AC/taxol Dose dense for 4 months, 33 rads and herceptin for 1 year (due to finish in 2 months).

On my first visit with the surgeon since that time, just recently, he told me that the core needle biopsy said i was 99% hormone positive, yet the surgery tissue results came back strongly 'hormone negative'. Based on this result, he has represented my case in a meeting with other health professionals. A re-testing was also done on both the core and after surgery tissue which produced the same results. Due to this, the oncologist and surgeon want to change my treatment to reflect the core hormone positive results as they think ths biopsy is the most accurate test of the two.

This new treatment will involve tamoxifen and either removing my ovaries (to decrease ER production) or monthly Zolodex injection to stimulate temporary hormone suppression. This is because I have gone back to being pre-menopausal, 6 months after the chemo.

I am in a real quandry as to what to do here and would love a second opinion and/or to see if anyone else has had a similar experience.

[Bronny]

After surgery, 18 months ago I was told I was hormone negative, HER2 + so my treatment included AC/taxol Dose dense for 4 months, 33 rads and herceptin for 1 year (due to finish in 2 months).

On my first visit with the surgeon since that time, just recently, he told me that the core needle biopsy said i was 99% hormone positive, yet the surgery tissue results came back strongly 'hormone negative'. Based on this result, he has represented my case in a meeting with other health professionals. A re-testing was also done on both the core and after surgery tissue which produced the same results. Due to this, the oncologist and surgeon want to change my treatment to reflect the core hormone positive results as they think ths biopsy is the most accurate test of the two.

This new treatment will involve tamoxifen and either removing my ovaries (to decrease ER production) or monthly Zolodex injection to stimulate temporary hormone suppression. This is because I have gone back to being pre-menopausal, 6 months after the chemo.

I am in a real quandry as to what to do here and would love a second opinion and/or to see if anyone else has had a similar experience.