Please explain.....

[Jean]

If a person is taking an anti estrogen drug - and they are becoming drug
resistance resulting from cellular cross talk and now having an increasze of Her2 receptors - how would they know this is happening and what can be done
to monitor this?

Regards,
jean

[Lani]

Carney WP. HER2 status is an important biomarker in guiding personalized HER2 therapy. Personalized Medicine, 2005. Vol. 2, No. 4, Pages 317-324
ABSTRACTThe human epidermal growth factor receptor (HER)2 oncoprotein has emerged as an important cellular target for the development of a variety of new cancer therapies. The method used to define the HER2 status is a major factor in determining who will receive these targeted therapies. The HER2 status can be determined by using either tissue tests to look at the primary tumor cells, or an enzyme-linked immunosorbent assay (ELISA) that measures the circulating levels of the extracellular portion of HER2 protein. Tissue test (immunohistochemistry and fluorescence in situ hybridization) results indicate that approximately 20–30% of patients with primary breast cancer have a HER2-positive tumor, whereas ELISA results demonstrate that an average of 45% (range: 23–80%) of metastatic breast cancer (MBC) patients can have an abnormally high (> 15 ng/ml) serum HER2 level, which is evidence that a HER2-positive tumor is present. Published studies show that the HER2 status of a breast cancer patient can differ both by the test method used and the time at which HER2 status is assessed. In this review, data will be shown that demonstrates that not all HER2 test results obtained from the primary breast cancer are correct, and that there is a population of patients categorized as HER2 negative by tissue tests that, in fact, have HER2-positive tumors. This observation has important therapeutic implications for breast cancer patients with HER2-positive tumors that are classified as HER2 negative, since they are not eligible for anti-HER2 therapy, such as trastuzumab. If a patient is found to have an elevated (> 15 ng/ml) serum HER2 level in MBC, then either the original tumor should be re-evaluated for HER2 status, or a metastatic lesion should be tested for HER2 positivity, to determine if the patient is eligible for anti-HER2 therapy. Studies have also shown that lack of adequate validation of a testing method can result in false conclusions concerning the HER2 status. If the goal of personalized medicine is to deliver the right treatment to the right patient at the right time then we need to ensure the validity of all test methods, regardless of whether they are for research purposes or are registered as in vitro diagnostics. In the case of establishing HER2 status, it takes more than one type of test to identify patients with HER2-positive tumors. It is highly likely that the introduction of additional targeted drugs to growth factor receptors or to angiogenesis targets will take a variety and combinations of tests to tailor the most appropriate therapy to the patient.

IF YOU ARE TALKING ABOUT A PRIMARY TUMOR WHICH WAS INITIALLY DIAGNOSED AS HER2+ THEN I THINK YOU MAY BE CONFUSING INCREASED NUMBERS OF HER2 RECEPTORS WITH UPREGULATION OF THE HER2 PATHWAY WHICH NEED NOT HAVE INCREASED NUMBERS OF HER2 RECEPTORS TO OCCUR.

HOPE THIS HELPS

[Jean]

Lani,

Thank you for the informative reply...
But, what I am trying to place clearly in my mind is not so much the Her2 factor after the primary tumor dx. but rather my question is addressing the hormonal status...For instance if a person is ER positive and PR negative, the absence of PR adds to the resistance to hormonal therapy and
AI therapy seems to have less resistance by blocking ER, but
how would one know if the AI is not working? Also - if the primary cancer
has spread isn't it possible that the orginial ER postive can change and
then be a ER negitive?

Regards,
Jean

[Becky]

Jean



I understand what you are asking. It is relevant that if one is PR neg but ER positive that resistance of an (anti) hormonal can occur. However, all that “resistance” means is that the cancer recurs. Way back when only ER and PR were tested for, doctors realized that women who weren’t strongly positive or only had one receptor positive tended to recur more than those who were strongly positive for both receptors. This is because these women tended to be positive for something else that wasn’t measured. In our case, Her2. For other women who are ER+ but PR neg but also Her2 neg, they are probably Her1+ (or positive for something else). Remember, your antihormonal still works but something else is also driving the cancer. Also, the Herceptin with an AI combo is excellent in the metastatic setting so I believe it is the one-two punch we need right now in the early adjuvant setting to really shut down 2 receptors at once (with the AI working well later too – it is PROVEN to work well alone (in HER2+ women) as well and it is PROVEN to work better for those that are ER+ but PR neg). Most cancers do not change pathology to go from positive to negative (but do change vice versa).

[Jean]

If a person is resistant to (anit) hormonal therapy is there anyway prior to
recurrance to determine if the treatment is not doing the job? I am also
questioning the aspect that if the treatment is not working it can cause increase of the Her2 receptors from cellular cross talk? So that the treatment is in fact causing the increase in the Her2. Am I off on this?

Thanks Becky, just thinking some issues through and I am not certain.

Warmly,
Jean

[Becky]

Dear Jean


I was always under the impression that there are no extra (or more) Her2 or other receptors, its just that they talk to each other since the hormone receptors are out of commission (that is what the "resistance" is but it is a misnomer. It is implying that the anti-hormonal isn't working when it probably is but other forces are causing the cancer to grow).

Theoretically, the Bayer Her2 serum test should work. If cancer is present, growing and reproducing, it would be shedding the extra cellular domain (I am just talking out loud here - maybe Lani or Heblaj01 can comment).

Real resistance might be if one knew that they were only hormone positive and the drug failed to work at all (estrogen was still high or one could later test to see if tamoxifen didn't cover the receptors).

I hope I helped you alittle bit.

[sally]

I was on Femara and my tumor markers went up consistantly and enough for my doctor to say that the cancer is active again. There is no sign of cancer on the scans. He took me off Femara and put me on Tamoxifen. It takes awhile to see if it is working. I guess the first two blood tests showed that the tumor markers went up which is normal when starting Tamoxifen. My last blood test showed that it is starting to go down. He said if it doesn't go down substantially the next time then more tests and try something else. I don't know if this helped you with your original question, Jean. In my experience my doc thought that the Femara wasn't working because of my tumor markers kept going up. Sally

[Jean]

Thank you Becky,
Just re-thinking the whole er-positive, pr - negative status. Was reading
some material and did not know the importance of the pr negative status.
Also considering the possible factor that pr negativity may reflect hyperactive cross-talk between ER and growth factor signaling pathways, esp. Her2.
Made me a bit uneasy - just trying to assemble all the factors in my head.

Warmly,
Jean

[Lani]

LOH means loss of heterozygosity which has to do with gene expression change within what is usually a gene pair.

ABSTRACT: Coexistence of the loss of heterozygosity at the PTEN locus and HER2 overexpression enhances the Akt activity thus leading to a negative progesterone receptor expression in breast carcinoma [Breast Cancer Research and Treatment]
Serine/threonine kinase Akt/PKB is known to regulate divergent cellular processes, including apoptosis, proliferation, differentiation, and metabolism. Akt is activated by a variety of stimuli, through such growth factor receptors as HER2, in phosphoinositide-3-OH kinase (PI3K)-dependent manner. A loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) function also activates Akt. It has recently been shown that Akt activation is associated with a worse outcome among endocrine treated breast cancer patients and that it also inhibits the progesterone receptor (PR) expression via the PI3K/Akt pathway in breast cancer cells. Therefore, the PI3K/Akt signaling pathway has recently attracted considerable attention as a new target for effective therapeutic strategies. In the present study, we investigated the relationship between Akt activation and either HER2 overexpression or PTEN gene alteration, as well as the PR expression. We analyzed the incidence of LOH at the PTEN locus in 138 breast cancer patients, using our new system for microsatellite analysis, called high-resolution fluorescent microsatellite analysis (HRFMA). We showed Akt activation to significantly correlate with HER2 overexpression or LOH at the PTEN gene locus while inversely correlating with the PR expression. In addition, when LOH at the PTEN gene locus and HER2 overexpression occurred simultaneously, the incidence of Akt activation and reduced PR expression was significant. The association between Akt activation and PR negative expression was observed even in the ER-positive cases. Our results suggest that simultaneous PTEN LOH and HER2 overexpression enhances Akt activation and may thus lead to a negative PR expression.
Will try to get the original article (I think this journal is open access for all)
but this will require the propellers to start rotating (Tom called me a propeller-head!)

The bottom-line is it is complicated and NOT YET FULLY UNDERSTOOD.

[Jean]

Lani,

Bless your Propellers!

A bit complicated - you say...### .. I will digest it a few more times.
Many heartfelt thanks.

Fondly,
Jean

[Lani]

If you look down the list of threads in the her2group you will see a post for advice from Grace Brophy who seems to have a somewhat similar history to yours. I suggested that in my addition to that thread, but I think you could
provide a lot more info than I could secondarily.

Once again, you are truly welcome!

[Jean]

Will Do Lani,


Jean