cut-off point used to determine her2 amplification to be lowered?

[Lani]

: Breast Cancer Res Treat. 2008 Jan 9 [Epub ahead of print]
New cutpoints to identify increased HER2 copy number: analysis of a large, population-based cohort with long-term follow-up.

Jensen KC, Turbin DA, Leung S, Miller MA, Johnson K, Norris B, Hastie T, McKinney S, Nielsen TO, Huntsman DG, Gilks CB, West RB.
Stanford University, Room L235, 300 Pasteur Drive, Stanford, CA, 94305, USA.
Background HER2 gene amplification and/or protein overexpression in breast cancer is associated with a poor prognosis and predicts response to anti-HER2 therapy. We examine the natural history of breast cancers in relationship to increased HER2 copy numbers in a large population-based study. Patients and Methods HER2 status was measured by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in approximately 1,400 breast cancer cases with greater than 15 years of follow-up. Protein expression was evaluated with two different commercially-available antibodies. Results We looked for subgroups of breast cancer with different clinical outcomes, based on HER2 FISH amplification ratio. The current HER2 ratio cut point for classifying HER2 positive and negative cases is 2.2. However, we found an increased risk of disease-specific death associated with FISH ratios of >1.5. An 'intermediate' group of cases with HER2 ratios between 1.5 and 2.2 was found to have a significantly better outcome than the conventional 'amplified' group (HER2 ratio >2.2) but a significantly worse outcome than groups with FISH ratios less than 1.5. Conclusion Breast cancers with increased HER2 copy numbers (low level HER2 amplification), below the currently accepted positive threshold ratio of 2.2, showed a distinct, intermediate outcome when compared to HER2 unamplified tumors and tumors with HER2 ratios greater than 2.2. These findings suggest that a new cut point to determine HER2 positivity, at a ratio of 1.5 (well below the current recommended cut point of 2.2), should be evaluated.
PMID: 18193353 [PubMed - as supplied by publisher]

[mts]

Amazing Stuff Lani !!!!!

[Hopeful]

Lani,

I am confused. Didn't the cut-off for being Her2+ get raised last year, from 10 to 30? I thought it was related to determining Herceptin sensitivity????

It seems like these two standards are measuring different things - this one that you posted, survival, the other, sensitivity to a drug. Clearly, there is not a 100% overlap between the two.

Hopeful

[Lani]

when they reviewed the adjuvant her2 studies they found that some people who responded to herceptin were really not that her2 + as they thought when they rereviewed their her2 findings.

As you know there are two ways tumors are usually classified as to her2 status, one is IHC where her2 is judged as 1+ 2+ or 3+ and the other is FISH where until now anything over a FISH ratio of 2.2 was considered her2 amplified. As FISH is more expensive to run, many studies qualified people who were her3+ or her2+, who subsequently underwent FISH testing and were found to be >2.2

Yes, I believe you are right in that these authors' intent at revisiting her2 positivity cut-off was to determine if there was a group with her2 positive, albeit to a lesser extent, which would impact adversely on their survival--and they found that there was.

The clinical implication of this and the reason I posted this, as itis attempting to identify a cut off marker which makes sure there aren't patients who could potentially could benefit from herceptin who are not being given the chance to receive it.

I have not heard of any attempts to increase any value for her2 which determined who would get herceptin (I am certain government and insurance company beancounters would love to, but at this year's SABCS they presented more interim results from the adjuvant trials which showed that the response to herceptin was not directly tied to the absolute value of FISH, as long as it was greater than the value admitting patients to the trial)

Just because I have not heard of it, certainly does not mean it doesn't exist, so feel free to post the information should you come across it.

By the way, I don't think they feel they have completely solved the mystery of why some patients responded to herceptin whom they did not expect to. I think some were even 1+if I recall correctly. As usual, we probably only understand a tiny portion of the puzzle.

[mcgle]

If this study is right, then I am more positive than I thought I was - FISH 2.71. Given that I received neither chemo nor herceptin, this is rather worrying ...

Mcgle (UK)

[Karen W]

If I remember correctly, my Fish score was 6.3.

Karen

[Hopeful]

Lani,

I think the article I was trying to recall was this one: http://jco.ascopubs.org/cgi/content/full/25/1/118

I think prior to this guideline change, 10% of the tumor had to stain positive for Her2 by IHC to be considered Her2+++, and it was raised to 30% (see http://jco.ascopubs.org/cgi/content-nw/full/25/1/118/T2 for the old standard and http://jco.ascopubs.org/cgi/content-nw/full/25/1/118/T4 for the revised one)

I have been curious about the change in standard, as I was dx in June of 2006, under the old algorithm, and wonder if the result would be different under the new one?

The point about Herceptin being of benefit to women who are less than Her2+++ by IHC has drawn interesting responses from the medical community. The initial responses I saw were to criticize the testing methods as being incosistent/unreliable in that they found results from different labs not easily reproducible. I think this may explain some instances but not all. I have seen more studies that are looking at how the signalling pathways are utilized by the cancer. It appears that Herceptin may block some signalling that occurs in patients that are not Her2+++, making this cut-off for determining Herceptin response unreliable.

The goal, I think, is to try to find out who might benefit from Herceptin and who will not. In this regard, I think there are more issues than just the magnitude of Her2+. For example, I have been reading papers lately about the interaction of all the Her family members and its relationship to outcomes for bc patients. It seems Her3 is a big influence in conjunction with Her2 combined with endocrine status. However, since all of the focus is on Her2 testing, we are losing a valuable part of the picture in trying to discern which Her2+ bc tumors are the most aggressive and amenable to certain types of tx when not testing for the other Her2 family members. It is unrealistic to expect that one marker will hold the key in a disease as complex as bc.

Hopeful

[Lani]

"nonresponse" to herceptin, but that is a hard thing to define. Does that mean 1)innate resistance, 2)acquired resistance or 3) just that another factor intervened which caused/allowe the patient's tumor to metastasize anyway.

elevated activated Akt could be a cause (even if herceptin stopped its activation, it could be activated on its own or via another pathway and result in the same endpoint)

biomarkers already known are , for example, low PTEN, or the inability of herceptin within the first few doses to decrease serum her2 ECD levels by ~20% (neither are absolute, but show a clear and significant trend in large numbers) The first two are examples of 1) and in the former case, might potentially also be a cuase of 2). Failure to block the ER and perhaps IGFR1
are said to be a cause of 2) and there are neoadjuvant studies by Spector, Bacus, et al to show that is the case with tykerb,also.

In the metastatic setting there is a 40% difference in the time required to "metabolize or clear" herceptin between those who do so slowly or quickly, so that could result in some failing herceptin because they just don't get it on the right schedule (that would fall in category 3)

So, as with everything else, it is not a simple picture like the RUBE GOLDBERG DIAGRAM I described yesterday. I have seen computer scientists at Stanford and Dr. Joel Gray at SABCS show diagrams of how they thing those parts of the network they know tie together with negative and positive feedback loops and the like and it would be an understatement to say it is a complicated picture. The reason to hope is that we now have very powerful computers working on the project. I think someone has posted how to donate one's computers "off time" toward finding a cure for cancer. Every
little thing helps!

[Rich66]

anything more on lowerng the FISH positive threshold?