Increasing Serum HER2 Test Results - Should I Panic

[Barbara]

I am looking for advice. I am Stage 2B and my Serum Her 2 test has gone from 5.5 in September, to 9.8 in November and is now 12.2 in January. The Serum Her2 neu lab test that I have run has a normal range of 5.1-13.5. I am now close to the upper level. During this time my CA 27-29 has been 9, 13, 20, 9, 10, 13 and 14. The CA 27-29 is run about every 3 weeks. Over the last two years since my diagnois my CA 27-29 has ranged up and down between 9 and 26 so I see nothing alarming in the CA 27-29. My last CEA was in November and it was .6. I am really worried about the Serum HER2 test as everthing I have read about early stage cancer says a medium of 254 days was found for 64% of the early stage patients from the time the Serum HER2 went over 12 and mets were present clinically.

I see my oncologist on Monday. I was thinking of asking him to repeat the Serum HER2 and do a CEA as a CA 27-29 was drawn today. Then if the Serum Her2 test remains high and or if my CEA is up I would like to ask for a pet scan and Brain MRI. If they come back clean I would like both repeated in three or four months (I am thinking of the medium time of 254 days to clinical mets after the Serum HER2 reaches 12).

What advice do you have for me? Should I be in a panic? Have any of you had this high of a Serum HER2 and did not have mets in the next seven months? I know many of you know far more than I do about both these tests and what may be a good course. I am presently receiving Herceptin infusions every three weeks.

Thank you for any advice you may offer.

Barbara

[julierene]

I didn't get all these tests, I just had to be in tune with my body for symptoms. For me, it was a backache that wouldn't go away. I never felt the mets in my liver though, I just thought I was getting sick cause I felt nauseated in the morning for a couple days before I had my bone scan.

If you can get your doc to give you a pet scan, some might consider that more than the normal routine. But I would try for it if you can. The brain MRI might be a tad premature. Maybe you could convince your doc for the PET scan first?

Brain mets are usually detectible from a routine exam right? Dizziness, nausea, blurred vision, headaches, or a few other small things. I told my onc I wanted a brain MRI after all my headaches, and he was about positive I didn't have brain mets, and he was right. He warned me that it would be an unnecessary test, and he was right. So you might be ok just starting with the exam for brain mets, and see if you can get the PET?

Could you cite the reference(or better still proivide a link) discussing the 254 day mean between Serum her2 value>12 and clinically detectable mets?
Thanks,
Lani

[Barbara]

Lani:

The article was published in Clinical Lab. 2004;50 (3-4):163-170. An abstract is available at www.oncogene.com/library/index.php. The author is Pichon, MF and is titled "Serum HER-2 extracellular domain (ECD) before first metastasis in 128 breast cancer patients".

I hope this helps.

Barb

unfortunately it included only 86 patients both her2neu positive and negative, so probably only 20 or so were her2 positive to start with. I have not seen the whole article yet, so will have to check out if they used the Bayer/Oncogene technology as they do at LabCorp

1: J Clin Pathol. 2006 Feb 3; [Epub ahead of print] Related Articles, Links

Serum HER-2 concentration in patients with primary breast cancer.

Kong SY, Kang JH, Kwon Y, Kang HS, Chung KW, Kang SH, Lee DH, Ro J, Lee ES.

National Cancer Center, Korea, Republic of.

AIMS: To evaluate whether serum HER-2/neu (HER-2) concentration is a valid index of HER-2 status in women with primary breast cancer and to establish a normal reference range for serum HER-2 concentration in Korean women. METHODS: We measured serum HER-2 concentration and performed immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) on tissue samples from 86 consecutive female patients, and we compared the results of the 3 data sets. We determined the cutoff value of HER- 2 concentration from the mean + 2 SD of values derived from the serum of 93 healthy volunteers. RESULTS: The IHC and FISH data were significantly associated with each other (P < 0.01), but neither showed significant concordance with the serum HER- 2 data. The cutoff value of serum HER-2 was 10.2 g/L, and the serum HER-2 concentration of patients with primary breast cancer ranged from 5.0 to 17.5 g/L. Only 5 patients showed a serum HER-2 value above the cutoff value. CONCLUSIONS: Serum HER-2 concentration cannot be substituted for IHC or FISH to evaluate HER-2 status, nor can it be used as a diagnostic tumor marker in primary breast cancer considering the low prevalence of serum HER- 2 elevation.

PMID: 16461567 [PubMed - as supplied by publisher]

The following article, which is fascinating in its entirety, describes her2 positivity in the primary tumor depending on what phase of the menstrual cycle the tumor was removed during...Ki67 also varies depending on the phase of the menstrual cycle. Perhaps this is why some her2+ patients do not respond to Herceptin--their tumor was felt to be more her2+ than it usually was due to the phase of menstrual cycle the surgery was performed in. Here is the abstract:


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

From reading the serum her2 literature in general and from comments by Walt Carney who invented and developed the test, its value has only been officially "validated" in metastatic patients and they are unsure of its meaning at all in premetastatic patients.
In those readings, I found the article I quoted above which, when read in its entirety, discusses premetastatic patients following chemo (which causes marked reduction of estrogen) or injection of leuprorelin (which causes a hormonally induced temporary "castration") caused serum her2 to increase markedly. It discussed the fact that her2 positivity in the primary tumor depends on which phase of the menstrual cycle it was removed during ie, the amount of estrogen influences the degree of her2 positivity. Similarly other articles I have read reveal the Ki67 level varies with phase of the menstrual cycle which coincided with the surgery. This full article discusses that as well and points out it has implications when deciding on treatment based on these values, which merely reflect a snapshot in time of a changing beast.

In this article they could not correlate increases in serum her2 neu in premetastatic patients with them subsequently developing mets, but the serum her2neu literature listed on the BayerOncogene website cites the article you previously brought to my attentiion on the lag time between serum her2 increase and mets.

Are you on antiestrogen therapy, particularly aromatase inhibitors--these lower your estrogen and thereby may increase your serum her2neu according to this article? Have you had your ovaries removed during/before your serum her2 went up? How long has it been since your chemo--are you post-menopausal? Are you on Herceptin --a decrease of 23% or more within 3 weeks of initiation of Herceptin treatment is felt to reflect efficacy of Herceptin IN METASTATIC PATIENTS ONLY EVEN IF THEIR BASELINE SERUM HER2 WAS <15.

Walt Carney did not think there was any indication that an increase in serum her 2 OF ANY VALUE <15 was anything to worry about in a premetastatic patient--that the knowledge of its values and fluctuations in premetastatic patients just isn't there yet.

I have previously discussed different labs doing the test.

Be certain to read your report as to where it was done and with what technique. When Specialty labs machine went down they farmed the test out to another lab, where results came back higher and the normal range was different. My one dealing with Lab Corp had the result come back 50% over the previous result--ARUP uses a manual rather than automated version of the test, but 3 weeks later it was back to the pre 50% increase level (but they have a slightly different normal range at 13.5%)

Gina is a master at titrating(finely adjusting) her treatment based on her serum her2 level , but then again, she is metastatic.

Beware, many of the labs print out on the results that the test is only approved/validated in the metastatic setting. LET'S HOPE THE INSURANCE COMPANIES DON'T LOOK AT THAT TOO CLOSELY or we will never have the results we need to find out if it is an accurate marker of tumor progression/response to treatment

[michele u]

Lani, That makes me feel alittle bit better. I had my ovaries taken out right aways, maybe that's why my sHer2 is 11.8

[Barbara]

Lani:

You did make me feel a little better. I am 60 y/o and and finished chemo in May 2004 and have been on Herceptin since that time. I am stage 2b. I still have my ovaries and was ER-and PR-and HER2 + 6.9%.

Thanks for your research.

Barbara

[Gina]

between serum her-2 and estrogen...I find that my serum her-2 and my CA 125 can be slightly higher the week just before my period and then ease back down the weeks after except during ovulation, when the same inverse relationship comes into play...fyi. As strange as it sounds, in my own body, I have found that my natural circulating estrogen tends to help me keep the serum her-2 in line, but also remember, my tumor and lesions were all ER - and PR -...different strokes for different folks..smile.

Take care,
Gina