prognosis for early stage node negative her2 defined:

[RobinP]

I have heard the question asked on these boards, just how large must the invasive her2+ cancer be to warrent treatment with Herceptin?And do node negative T1 lesions really need Herceptin treatment? I find such questions very interesting because I had a very small 4mm invasive with only less than a micromets in the first node.

Perhaps the below link will convince some of you that it is the overexpression of her2 and mitotic index that may be more significant than the amount of invasive cancer involvement and the spread to the node that will ultimately determine prognosis. As the,"the six-year rate of relapse in early stage node negative bc in the below study was 40% for patients with highly positive tumors and 26% for those with weakly HER-2-expressing tumors ."Accordingly, the amount of hER-2 expression identifies a subgroup of node-negative breast cancer patients with the worst prognosis, who are candidates for specific intensive adjuvant therapy and might I add myself targeted therapy with herceptin as well.

Clearly, from all indications from the articles below, it appears we should be examining our pathology reports, looking at the CEP/Her2 ratio score for overexpression and at proliferation index for high tumor growth rates.

PS. I believe that a CEP/Her2 ratio over 4 is defined as highly overexpression of her2 and anything less than 4 is weakly overexpression of her2. Note the following from the full abstract,Her2 expression and cell proliferation: prognostic markers in patients with node-negative breast cancer:



"We tested the pure prognostic value of HER-2 overexpression, according to internationally proposed guidelines,10,11 on the largest case series of node-negative breast cancer patients studied up to now. We failed to find a relevance of any cutoff value of HER-2 overexpression on RFS-risk free survival. However, a breakdown analysis permitted us to attribute a discriminant prognostic power to HER-2 overexpression within the subgroup of patients with rapidly proliferating tumors. In particular, patients with tumors in which a high proliferative activity was associated with HER-2 overexpression showed a risk of relapse approximately two times higher than that observed for patients with rapidly proliferating but weak HER-2-expressing tumors, or for those with slowly proliferating tumors regardless of HER-2 expression.

In conclusion, HER-2 expression and cell proliferation would seem to provide complementary prognostic information for node-negative breast cancer patients. Obviously, the clinical use of HER-2 expression requires confirmation of our results in large prospectively planned studies, such as those already performed for cell proliferation.9,20 "
Here's the abstract summary in full:

Her2 expression and cell proliferation: prognostic markers in patients with node-negative breast cancer.

Citation:

J Clin Oncol, United States; Vol 21, No 14 (Jul 15, 2003): pp. 2708-12

Affiliation:

Dept of Medical Oncology, Pierantoni Hospital, via Forlanini 34, 47100 Forlì, Italy. a.volpi@ausl.fo.it.

Authors:

Annalisa Volpi, Oriana Nanni, Franca De Paola, Anna Maria Granato, Annita Mangia, Franco Monti, Francesco Schittulli, Mario De Lena, Emanuela Scarpi, Paola Rosetti, Manlio Monti, Lorenzo Gianni, Dino Amadori, Angelo Paradiso

PURPOSE: We analyzed the clinical relevance of HER-2 expression, widely investigated in breast cancer but with contradictory results, in the largest case series of node-negative breast cancer patients investigated to date. PATIENTS AND METHODS: The pure prognostic value of HER-2 expression was investigated in 529 patients treated with locoregional therapy alone until early relapse. Proliferative activity was evaluated as [3H]thymidine labeling index and HER-2 expression by immunohistochemistry. All biologic determinations were conducted within the context of an intra- and interlaboratory National Quality Control Program. RESULTS: HER-2 expression was not related to relapse-free survival in the overall series but was a significant discriminant of prognosis in the subgroup of patients with rapidly proliferating tumors. Six-year rate of relapse was 40% for patients with highly (> or =30%) positive tumors and 26% for those with weakly HER-2-expressing tumors (P =.039). CONCLUSION: HER-2 expression in association with proliferative activity identifies a subgroup of node-negative breast cancer patients with the worst prognosis, who are candidates for specific intensive adjuvant therapy.




PS Let me just define proliferative activity of your tumor may be found by looking at the grade and mitotic index. As you know, the higer the mitotic index, the faster the tumor grows. See below article for information on that as well.


Prospective multicenter validation of the independent prognostic value of the mitotic activity index in lymph node-negative breast cancer patients younger than 55 years.

Citation:

J Clin Oncol, United States; Vol 23, No 25 (9/2/2005): pp. 5993-6001

Affiliation:

Department of Pathology and Epidemiology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands. baja@ier.no

Authors:

Baak, van Diest, Voorhorst, van der Wall, Beex, Vermorken, Janssen

[img]/portal/beans/virtualmeeting/images/clear.gif[/img] [img]/portal/beans/virtualmeeting/images/clear.gif[/img] [img]/portal/beans/virtualmeeting/images/clear.gif[/img] PURPOSE: To validate the independent strong prognostic value of mitotic activity index (MAI) in lymph node (LN) -negative invasive breast cancer patients younger than 55 years in a nationwide multicenter prospective study. PATIENTS AND METHODS: Analysis of routinely assessed MAI and other prognosticators in 516 patients (median follow-up, 118 months; range, 8 to 185 months), without systemic adjuvant therapy or previous malignancies. RESULTS: Distant metastases occurred in 127 patients (24.6%); 90 (17.4%) died as a result of metastases. MAI (< 10, > or = 10) showed strong association with recurrence (hazard ratio [HR], 3.12; 95% CI, 2.17 to 4.50; P < or = .0001) and mortality (HR, 4.42; 95% CI, 2.79 to 7.01; P < .0001). The absolute difference in 10-year Kaplan-Meier estimates of time to distant recurrence as well as survival was 22% between MAI less than 10 versus > or = 10. This effect was independent of age, estrogen receptor (ER) status, and tumor diameter (which were significant prognosticators). In multivariate analysis with regard to patient age, tumor diameter, grade, ER status, and the St Gallen criterion, MAI proved to be an independent and the strongest prognosticator. Tubular formation (TF) and nuclear atypia (NA), as constituents of (expert revised) grade, had no (for TF) or limited (for NA, P = .048) additional prognostic value to the MAI. In the group with MAI less than 10, MAI less than 3 versus more than 3 had additional value but the classical threshold of 0 to 5 v 6 to 10 did not. With this additional subdivision of MAI as less than 3, 3 to 9, and more than 9, NA lost its additive prognostic value. CONCLUSION: The MAI is the strongest, most widely available, easily assessable, inexpensive, well-reproducible prognosticator and is well suited to routinely differentiate between high- and low-risk LN-negative breast cancer patients younger than 55 years.

[Montana]

Would this be the mitotic activity index from my path report:

".....and has "6 mitoses/10hpf" (score 2)" ?

As far as I know, I never had the FISH preformed, only the IHC which was 3.6. Would thiese results put me into the 40% 6 -year rate of relapse? I was node negative.

Sue

[RhondaH]

that less than 4 was weakly expressing AND that Herceptin may not have any (or minimal impact)...I'm 3.16 by FISH. In some regards, I "somewhat" consider myself a triple negative w/ a little HER2. Thank you for the article Robin. I TOO was Stage 1, node negative and no history of cancer in my family (both my grandmothers lived to age 91 and died of natural causes).

Rhonda

[AlaskaAngel]

Thank you so much for continuing to explore the issues from the chat Sunday, in trying to determine factors that help with decision-making for early stage bc.

I assume the studies are looking at the broad range of patients over time regardless of whatever treatment they may or may not have had, and since most do have chemo (?) then this would apply despite chemo. Considering that the higher the mitotic rate, the better chemo supposedly works...IF the correct chemo is utilized, and since I was considered HER2+++ I received 6 courses of CAF (Adriamycin being considered to be the most useful for HER2). It is very interesting. I was treated just prior to the changeover to the newer generation chemos using a taxane and I continue to question why that in itself is not considered a "higher risk" factor for me, since they can't have it both ways; either the newer therapies are significantly better (leaving me at higher risk) or they aren't. I also missed out on dose-dense. But if these studies looked at long-term then they would be using the data from those treated with older chemo's, like me?

I probably don't even need the mitotic rate to tell me my cancer was fast-growing, since it measured 1.0 cm by ultrasound initially and 2 1/2 months later it measured over 1.5 cm by ultrasound. Mitotic rate was listed on the path report only as "intermediate to high".

AlaskaAngel

[AlaskaAngel]

These patients at most were treated with just loco-regional therapy (to belatedly answer my own question! That is what giving up caffeine does to me I guess.)

A.A.

[RobinP]

Just a few comments concerning the above posted article on her2 expression and cell proliferatioin…



HER-2 Expression is NOT defined by CEP her2 ratio as I originally thought. Once I read the entire abstract, I realized her2 expression is defined as below. Also, the proliferaton index is specifically defined in terms of TLI which is also defined below for you.
Immunoreactivity was expressed as the percentage ratio between the area of immunopositive tumor cells and the entire area of invasive neoplastic tissue. In particular, the percentage values were subdivided into 10% classes from 10% to 90%, with a further subdivision in 5% classes for values less than 10 or more than 90. Note in the table low expressioin was 18-28 and high was 23-37. (I know it doesn’t make sense, there is a cross over here??????????????)

TLI
thymidine-labeling index (TLI),9 which has been shown to be a consistent and powerful prognostic factor over time.

Also, in the first article in my orginal post, 2/3s of the study group had a primary tumor of 2cm or less. Note many of us are less than 1cm, being early stage.



http://www.jco.org/cgi/content/full/21/14/2708 link to the entire abstract

[CherylS]

Sorry for what is probably a silly question, but is locoregional treatment referring to lumpectomy and radiation alone?

"In particular, patients with tumors in which a high proliferative activity was associated with HER-2 overexpression showed a risk of relapse approximately two times higher than that observed for patients with rapidly proliferating but weak HER-2-expressing tumors, or for those with slowly proliferating tumors regardless of HER-2 expression."

"The clinical outcome was substantially worse for the subset of patients with tumors in which a high proliferative activity was coupled with high HER-2 expression, compared with that of patients with weak expressing HER-2 or highly HER-2 expressing but slowly proliferating tumors (P = .002)."

Is this saying that if you have a low mitotic index (say 1) and high her2 score (say 6.5) that her2 is not a strong indicator and that mitotic activity is a better indicator of disease free survival?

I will try to get the original article, but in the meantime it seems we are comparing apples and oranges. The method of her2 detection here was ihc ("immunohistochemistry"). There have been many studies showing that FISH is the more accurate method for detecting her2 overamplification and that a large percentage of ihc2+ tumors are, in fact, FISH negative. IT seems that Herceptin's effect is best in tumors which are FISH positive--the results in trial before FISH was used as the determinant of her positivity were considerably worse ie Herceptin does not work as well on IHC 2+ but FISH -patients.

Ki67 is generally felt to be the best test of proliferation ("mitotic index" means literally an index of how often the cells are dividing), but it is not done everywhere and not equally well everywhere.

Interestingly, in the development of the ONCODX test of the 21 genes chosen to evaluate --one was estrogen receptor, one was progesterone receptor, one was her2neu and a neighboring gene which almost always goes with it..the vast majority of the other genes were those indicating proliferation. Thus at San Antonio I heard it said by Dr. Slamon and others that one could save the $3500 by having a well-performed her2 by FISH, ER, PR and Ki67--perhaps RobinP's recommended company Targeted Molecular Diagnosistics could provide a second opinion service testing those 4 markers for less than their normal $190 per marker for those on this board. That would particularly help our non US members who have trouble convincing their doctors, or the National Health Service or equivalent, to test their tumor, or if they doubt the testing is done well locally.
The reason the ER and PR are important is that they are QUANTITATIVELY decreased in her2 + tumors ie their percentage may be high, but their absolute amount tends to be low which might become important in treatment choices.

To put Robins article in perspective--that was in 2003 in Italy. Those were the methods they were using then to test.

I hope we never again get studies with these sorts of figures--ie, that everyone with a her2 tumor will be treated with herceptin +/- chemotherapy or other systemic treatment rather than getting "locoregional treatment alone" (I think the thinking was that it was SIZE that mattered and small tumors just didn't need additional therapy--there are many on this website who have proven them wrong)

Thanks for all the info Robin!

Lani

[AlaskaAngel]

That is how I interpret it. I guess it could also refer to the new suggested potential use of chemo directly to the breast intraductally.

AlaskaAngel

[Julie2]

My Ki67 is 11%. So it was mentiond in my path report as borderline (Anything above 20% is high). But since I had supraclavicular node positive, my onc didn't think ki67 is of any great significance in my prognosis. At the same time I was very surprised to learn that another patient with 4cm tumor and ki67 70% had negative nodes. I am really confused about this prolifiration factor.Julie

[RobinP]

To Unregistered who asked-"Is this saying that if you have a low mitotic index (say 1) and high her2 score (say 6.5) that her2 is not a strong indicator and that mitotic activity is a better indicator of disease free survival"



Answer- I think the article is merely suggesting that if you have a high proliferation correlated with a high percentage of her2, than your prognosis is worse than if the proliferation index was low. That's not to say that high her2 and low proliferation index is insignificant though, and it's not to say that her2 is less of a prognostic marker than a mitotic index.



Other comments I have concerning the initial posted article is that 500 study participants was a small study. Additionally, I did not favor the method of her2 testing with IHC. I would have rather seen FISH testing, as Lani suggested. However, one thing is clear; proliferation index is a strong prognostic predictor, especially associated with her2.



Hopefully, we will see more and larger studies for very early stage her2+, node negative bc that will predict prognosis for this group clearly. We all have a pretty good idea that larger her2+ breast cancers, with and without nodal involvement are not favorable things to have. But what about node negative small invasive her2+bc such as T1 lesions; what is exactly the prognostic significance of this subset?

Nothing is ever simple!

Not only is serum Her2neu is increased by ovarian oblation by chemotherapy or leuprorelin injections, but tumor her2neu and Ki67 values depend which phase of the menstrual cycle the primary tumor is removed in. Here is the abstract--full article readable:

1: Breast Cancer Res Treat. 2003 Aug;80(3):245-55.
Related Articles, Links

Upregulation of HER-2/neu by ovarian ablation: results of a randomized
trial comparing leuprorelin to CMF as adjuvant therapy in node-positive
breast cancer patients.

Luftner D, Jung A, Schmid P, Geppert R, Kienle E, Wernecke KD, Possinger K;
Takeda Adjuvant Breast Cancer Study with Leuprorelin Study Group.

Medizinische Klinik und Poliklinik II, Schwerpunkt Onkologie und
Hamatologie, Universitatsklinikum Charite, Campus Mitte,
Humboldt-Universitat zu Berlin, Berlin,Germany.
Diana.Lueftner@rz.hu-berlin.de

PURPOSE: HER-2/neu oncogene expression is modulated by an
estrogen-sensitive binding site in the HER-2/neu promoter. Utilizing the
circulating antigen of HER-2/neu in serum (sHER-2/neu) as a surrogate marker
we investigated whether ovarian ablation by adjuvant therapy leads to an
upregulation of HER-2/neu in breast cancer patients. PATIENTS AND METHODS:
The analysis was done on sera from premenopausal, node-positive,
hormone-receptor positive patients randomized in a multi-center trial. The
study was designed with patients receiving either 11.25 mg of leuprorelin
s.c. every 3 months over 2 years or CMF chemotherapy for 6 cycles. Sera,
available from 80 patients in the leuprorelin arm and from 53 patients in
the CMF arm, were collected at 0, 3, 6, 12, 18, 24 and 30 months. sHER-2/neu
was measured using a standardized ELISA assay that has an upper limit of
normal of 15 ng/ml. sHER-2/neu results were correlated to the levels of LH,
FSH and estradiol as indicators of ovarian ablation and to the tumor marker,
CA 27.29. RESULTS: During estradiol deprivation, sHER-2/neu levels increased
significantly by more than one third from 8.1 ng/ml to 11.0 ng/ml (p <
0.0001) in both treatment arms. The most pronounced relative increase
occurred within the first 3 months (p < 0.001). In only 2.7% (16/587) of
sHER-2/neu measurements, the sHER-2/neu results were elevated above 15
ng/ml, confirming the upper limit of normal for breast cancer patients
irrespective of their menopausal status. At month 30, the sHER-2/neu level
started to decrease in the leuprorelin arm, reflecting reversible castration
and estradiol reconstitution. Conversely, CA 27.29 levels did not show a
trend over time, indicating that sHER-2/neu changes were of a regulatory
nature and were not merely a reflection of increasing residual disease.
CONCLUSION: Our study demonstrates the upregulation of HER-2/neu during
ovarian ablation. These results are consistent with data showing that the
percentage of HER-2/neu positive tumors, evaluated by standardized
immunohistochemistry on the primary tumor, is significantly increased during
the follicular phase of the menstrual cycle (Balsari et al., Am J Pathol
155: 1543-1547, 1999). Regulatory processes at the HER-2/neu gene should be
considered when prescribing specific therapy for breast cancer.

Publication Types:
• Clinical Trial
• Randomized Controlled Trial

PMID: 14503797 [PubMed - indexed for MEDLIN

[RobinP]

Interesting Lani. However, most of us that are her2+ are er,pr, negative, not postivie as the patients in this study. Not surprisingly, you would expect to see up regulation of her2 in er,pr+ cancer when estrogen is deprived as the cancer seeks another pathway of growth as opposed to the estrogen pathway.However, this is not to say that declining estrogen levels is the CAUSE of her2 bc. No if this be the case then all er,pr+ bc that is her2- would convert to her2+ when an antiestogen would be given and we know this does not happen.