FISH result Equivocal whereas IHC was - .9

trigeek · February 2008

trigeek · February 2008

Her2 gals I need you help.. as I am totally confused and just got this pathology report a friday evening ( will reach out for my oncologist next week)

I had my biopsy on 8/1/07 and the result of the Her2 with IHC was .9 so it was stated that I am negative.

However as I was seeking a second opinion from another major cancer center for my future treatment options ( rads) they requested my slides and following is the report that they faxed to me...

I am not sure what this really means, IHC was not borderline it was .9 so I do not even know why they decided to do the FISH. What is the next step for equivocal FISH result ? how can the IHC be clearly negative ( .9) and FISH be equivocal -- which I am not sure what that even means in this context arghhh...

HER2/neu by FISH: EQUIVOCAL

Ratio of HER2/neu signals to chromosome 17: 1.7
The average of Her-2/neu copies per cell: 1.1
The cutoff point for reassessing Her-2/neu gene amplification is a her-2/cen17 ratio of 2.0

The specimen is considered EQUIVOCAL for the Her-2/neu gene.

This result falls within the range of 'equivocal" ( 1.8-2.2) as defined by the 2007 ASCO/CAP guidelines. Comparion with results from another methodology such as immunohistochemistry may be of benefit. -- WELL IHC SAID .9 ???

Thanks for your input in advance !

LittleFlower · February 2008

Don't know what the report means exactly, but looking up the definition:

of uncertain nature or significance;

Maybe it agrees with the IHC that it is not Her2 overexpressive???

wish i knew with certaintly, but sounds like FISH was inconclusive in determining that the sample is her2 positive.

These reports can really take up alot of our time and thoughts can't they?

Keep us posted,

LittleFLower

TenderIsOurMight · February 2008

Your situation gives me pause.

It appears that your equivocal results on HER2/neu testing may prompt a second (or third look) at your individual situation, particularly by a clinician expert in HER2 positive disease states.

I can think of two scenerios for discussion:

a) Do equivocal results themselves merit Herceptin treatment under close supervision, due to the known benefits of decrease in recurrence with this monoclonal antibody?

b) Being ER/PR+ with equivocal HER2+ status is Herceptin treatment of merit? This point is driven by data suggesting ER+ status crosstalks with HER, and is best left to discussion with your doctors.

Here then is the ASCO guidelines on HER2 testing, specifically discussing "equivocal" states.

"American Society of Clinical Oncology-College of American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer

Antonio C. Wolff*, M. Elizabeth H. Hammond*, Jared N. Schwartz*, Karen Hagerty, D. Craig Allred, Richard Cote, Mitchell Dowsett, Patrick L. Fitzgibbons, Steven Gutman, Wedad Hanna, Patricia Keegan, Amy Langer, Lisa M. McShane, Soonmyung Paik, Mark D. Pegram, Edith A. Perez, Michael F. Press, Anthony Rhodes, Catharine Sturgeon, Sheila Taube, Raymond Tubbs, Gail H. Vance, Marc van de Vijver, Thomas Wheeler, Judy Yost, and Daniel F. Hayes*

*ASCO/CAP Expert Panel Co-Chairs

Purpose: To develop a guideline to improve the accuracy of human epidermal growth factor receptor 2 (HER2) testing in invasive breast cancer and its utility as a predictive marker.

Methods: The American Society of Clinical Oncology and the College of American Pathologists convened an expert panel, which conducted a systematic review of the literature and developed recommendations for optimal HER2 testing performance. The guideline was reviewed by selected experts and approved by the board of directors for both organizations.

Results: Approximately 20% of current HER2 testing may be inaccurate. When carefully validated testing is performed, available data do not clearly demonstrate the superiority of either immunohistochemistry (IHC) or in situ hybridization (ISH) as a predictor of benefit from anti-HER2 therapy.

Recommendations: The panel recommends that HER2 status should be determined for all invasive breast cancer. A testing algorithm that relies on accurate, reproducible assay performance, including newly available types of brightfield ISH, is proposed. Elements to reliably reduce assay variation (for example, specimen handling, assay exclusion, and reporting criteria) are specified. An algorithm defining positive, equivocal, and negative values for both HER2 protein expression and gene amplification is recommended: a positive HER2 result is IHC staining of 3+ (uniform, intense membrane staining of > 30% of invasive tumor cells), a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus or a FISH ratio (HER2 gene signals to chromosome 17 signals) of more than 2.2; a negative result is an IHC staining of 0 or 1+, a FISH result of less than 4.0 HER2 gene copies per nucleus, or FISH ratio of less than 1.8. Equivocal results require additional action for final determination. It is recommended that to perform HER2 testing, laboratories show 95% concordance with another validated test for positive and negative assay values. The panel strongly recommends validation of laboratory assay or modifications, use of standardized operating procedures, and compliance with new testing criteria to be monitored with the use of stringent laboratory accreditation standards, proficiency testing, and competency assessment. The panel recommends that HER2 testing be done in a CAP-accredited laboratory or in a laboratory that meets the accreditation and proficiency testing requirements set out by this document."

From: http://www.asco.org/portal/site/ASCO/menuitem.c543a013502b2a89de912310320041a0/?vgnextoid=e73791f49e96d010VgnVCM100000ed730ad1RCRD&vgnextfmt=default

And here is an eligibility statement of HER in a clinical trial that got me thinking on your situation:

"Patients will be considered to be eligible if HER2 expression is documented by one of the following methods: - IHC, 1+, 2+, or 3+ levels of expression or -Gene amplification [FISH], positive as determined by the laboratory performing the test or - Serum HER2 ECD greater than or equal to 15 ng/ml". (Note, this is just to illustrate a clinical trial example).

Our personal oncologist's carry great knowledge on HER2 disease states. As one can see though, you fall in a gray zone which may benefit from the "two heads" theory of help. Hope this helps.

All the best to you and other HER ladies.

Tender

Anonymous · February 2008

Hi trigeek...I am also "borderline," having had a questionable, but still borderline IHC and a pretty clearly negative by FISH (can't recall my numbers). After chemo, my oncs allowed me to research and decide for myself whether I wished to take Herceptin. When I discovered that the potential for heart damage seems to be greater among heavy exercisers who had also had Adriamycin, my decision was made and I turned down the Herceptin. My oncs fully supported that decision. I know that your exercise regime is even heavier than mine, so my question is this: did you have Adriamycin too?

Another aid to your decision would be for them to re-FISH your tissue, so maybe your doc can order the test re-done?

~Marin

trigeek · February 2008

Tender thank you soo much for your detailed information, I have written a letter to my oncologist and faxed it along with my path report requesting the slides to be retested if he finds appropriate.

Marin, you are bringing up a really important point, yes I did have the red devil and I really do not want to do Herceptin for the reason you have stated. My IHC was clearly negative, but FISH is Equivocal -- which i heard is different than borderline..

"It is also clear from the panel discussion and literature review that patients with equivocal HER2 test results constitute a poorly studied subgroup with uncertain association of test scores to benefit from HER2-directed therapy.60 The panel suggested that further studies of this patient group would be promoted by defining these test results as equivocal or borderline. The panel elected to use the term equivocal to avoid confusion with borderline positive and borderline negative terminology which is sometimes used in the interpretation of FISH assays. Equivocal results of a single test require additional action which should be specified in the initial report. Equivocal IHC samples must be confirmed by FISH analysis of the sample. Equivocal FISH samples are confirmed by counting additional cells or repeating the FISH test. If FISH remains equivocal after additional cells counted or assay repeated, confirmatory IHC is recommended so that HER2 protein expression is known for the sample with true equivocal gene amplification status. "

It is interesting that there was no response from other HER gals, I wonder if this means that no one has had an Equivocal result from the test ?

Cathy-CA · February 2008

I had equivocal from the FSH, but when it was retested with IHC, it came out 3.1 or overexpression. Fortunately, I had this information before we made the final decision on what chemo regimen to use, so elected to do taxotere and carboplatin rather than ACT to try to avoid the heart problems associated with adriamycin and herceptin. I have only had one round of treatment and go for my next a week from today, so can't tell you anything about longer term impact.

trigeek · February 2008

Cathy, thanks for the input. I thought that IHC could only be done on fresh tumor samples ?

Did you have IHC before FSH ? What was the value then ?

Thanks a bunch..

Cathy-CA · February 2008

No, I had FSH first. On the report for the initial biopsy, the Her2/cen 17 ratio was 1.3. The surgeon had told me that the initial biopsy was pretty small, so that things could change once she took out the tumor and it was biopsied in full. I can't seem to find the FSH report from that, but I was told it was equivocal. When I met with the oncologist, she said she had the pathologist retest and that's the IHC report I have with a score of 3.1. It looks like it was sent out to a different lab rather than done inside the hospital and there's a reference to "Breast Cancer Prognostic Panel by ChromaVision ACIS Assisted Quantitative Image Analysis". This is a semi-automated system that is supposed to be more accurate than the manual count that a pathologist does, so that could explain the difference.

trigeek · February 2008

Thanks Cathy, either I am not thinking right or things definitely went interesting regarding my surgical pathology report.

When I looked at my surgery report, it says that the ER/PR/Herneu was done on the previous biopsy sample.

Although I have not checked into it yet it just does not seem right that they would not retest it , so in essence they went with the initialy core biopsy report and did not bother doing another analysis re: ER/PE/Her of the main tumor. But when the slides were sent to the other center they did the FSH test on unstained slides.

I am really getting frustrated, who is supposed to be taking care of me ? Was I supposed to ask whether they would do another biopsy of the mastectomy ?

trigeek · February 2008

My biopsy report says:

ER,PR,HER2Neu,p53 and Ki67 were performed by IHC on formalin-fixed paraffin processed tissue in conjunction with the ChromaVision ACIS... Detection system for HER2Neu is dextran polymer linking system and clone is Herceptest kit.

Cathy-CA · February 2008

I'm not sure who is responsible for requesting additional testing. My surgeon is a breast cancer survivor herself, so asks for everything. However, she deferred to the pathologist as to what she wanted to do with the equivocal report. Since I am ER- and PR-, I think the pathologist pushed to see if they could get a more definitive answer on the HER2/neu since that would provide a clearer treatment path. Keep asking your doctors questions until you get an answer with which you are comfortable.

TenderIsOurMight · February 2008

Trigeek,

No, you are not responsible for asking for any specific test on your mastectomy! How would a patient know? There are pathology procedures/guides in place and standardized just for this. Regrettably, the IHC/FISH testing for HER2/neu has required small labs or not qualified labs with quality performance issues to be addressed, and added confusion and worry along the way.

ER/PR/HER2 tests should not be done on initial core biopsies for various reasons. If they are, they definitely should be re-checked on the tissue that came for the final pathology. Are you saying they were not repeated in your case or possibly that it's just too confused to know?

I did see your question about IHC performance. My understanding is that this technique (immunohistochemical, involving an antibody to an antibody, and involving staining that attaches to the breast cancer cell) is done on formalin fixed material. In other words, it does not require fresh breast tissue.

It sounds like this will be getting straightened out with you shortly. More waiting....

Tender

trigeek · February 2008

Tender it seems pretty clear that they did not do another pathology on the tissue that came out from mastectomy.

Here is what my Surgical Pathology report says:

ER/PR/HER2Neu: Performed on previous biopsy sample(S-07-29512,08/01/2007)

08/01/2007 -- is my core biopsy date. The biopsy itself though was done in the same Hospital by my surgeon maybe thats why they felt they did not need to do it again ?

Still waiting for doctors feedback, the nurse said that he reviewed the documents sent to him at night after hours.

I am so sick of trying to make treatment decisions ( lumpectomy-mastectomy, axillary node dissection or not, rads or not ) and now this. I always prided myself for making sound decisions, maybe this illness was brought upon me to make me more humble, and tell me that I really do not want to have control over everything.

Sorry..

Aylin -- waiting in the trenches.

twink · February 2008

Aylin,

I had to specifically request retesting of the tumor after my bilateral mastectomy. The pathology report following the surgery simply made reference to the initial pathology report from the incisional biopsy ('Reported as ER/PR and HER2/neu negative').

The first test (IHC) results: 0/Negative

The second test results: 2+/Equivocal (IHC); FISH 1.6/Negative

I had to insist on the second test following my surgery otherwise, they were going to let the results from the earlier biopsy ride.

trigeek · February 2008

Received a call from my oncologist today, following is a summary of what he said:

He started out saying that he is very confident of their HER2 expertise saying that they were one of the pioneers who worked with UCLA. -- > established credibility.

The tumors are not heterogeneous so different parts might show different results ( IHC showing HER-, whereas FISH showing Equivocal). The result is not very surprising and it happens a lot.

From these 2 test results apparently my HER+ is not established and is not highly positive.
Herceptins benefit is directly proportional to the degree of HER positivity so it will not be very beneficial for me since none of the tests revealed high counts.

Even if I was proven HER+ at this point my treatment plan would not change because the benefit I will gain from Herceptin will be greatly be offset and exceeded by the potential cardiac toxicity that a treatment containing Adriamycin topped by Herceptin could cause.

The chemo regimen I received Dose Dense 4 X AC and 4 X Taxol is a perfect chemo for a possible HER+ situation.
( here I have to thank him because I had wanted to drop the Taxol, since the research establishing the fact that HER- patients had not benefited from taxol was published at the beginning of my treatment, and he had not let me drop it )

He also supported his view of removing my port during surgery ( the other oncologists usually want to leave it in for 2 years in case there is a recurrence)
- To leave the port in is a negative thought.
- The likelyhood of getting an infection or other complication related the port is higher than the risk of recurrence.
- I will be getting surgery anyways (getting the expanders replaced by silicone implants)

The radiation delay ( I will be starting radiation about 8 weeks after my last chemo) did not worry him for my situation either.

So he pretty much put my mind at ease which is what I desperately needed now. Cool I am happy that I was able to believe him.

Thanks for bearing with me gals !

LizM · February 2008

My situation was reversed in that I had an IHC of 2+ and a negative FISH of 1.2 from my biopsy. I believe it is pretty standard practice not to redo the ER/PR and Her2 after final tumor is removed and to go with the biopsy results. I say this because my biopsy, surgery, final path was all done at Johns Hopkins. My oncologist is one of the authors of the above article from ASCO on proper her2 testing. He was very confident with my biopsy result but I wasn't. To give me peace of mind almost a year after my surgery he had my positive lymph node (he figured testing the node was by best way to go) tested and it came back as IHC of 0 and FISH of 1.2 negative. I did give me peace of mind to have it retested but also gives me peace of mind knowing I had dose dense AC and Taxol.

LizM · February 2008

Trigeek, I also wanted to comment that I too waited 7 weeks after chemo before starting rads (was planning to do implant exchange but had to cancel due to low WBC and ended up doing implant exchange after rads) and my rads oncologist was perfectly fine with it. Also, I had my her2 retest done almost a year after my surgery and after chemo and rads for whatever it is worth. My oncologist puts a great deal of emphasis on my peace of mind.

FISH result Equivocal whereas IHC was - .9

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