Odd HER2 test results/odd onc. recommendation (questions!)

Hi CBWeather:

I am assuming you have an actual copies of the original full report of the pathologist for the surgical pathology, and all appendices or supplements, including the HER2 test results (IHC, SISH).

Could you please clarify something? You stated: "Again, she was ER-, PR-, and HER2+." Are you saying that, after conducting IHC and SISH tests and repeating them several times, the Pathologist characterized her overall status as "HER2-positive" ?

BarredOwl

Hi CBWeather:

Thank you for the additional information. The lack of response from HER2-positive members may be because this seems to be an unusual case.

I had a very different diagnosis than your mother and had insufficient tissue for HER2 testing (not even tested), so please consider this as information only from a fellow-patient layperson.

Confirm everything with your providers to ensure accurate and current professional advice.

This is my understanding:

Diagnosis:

Invasive apocrine carcinoma, with apocrine DCIS.

Invasive disease is hormone-receptor negative (ER-negative, PR-negative), pT1b (0.9 cm is the largest dimension), with no lymph node involvement (pN0), and distant metastasis is not applicable. Overall grade 2. Tumor focality is single.

DCIS disease is 6 mm, grade 3.

Biopsy: ER- and PR-. Copy of pathology report indicates HER2 testing requested, but does not contain the result. No copy of HER2 test results was received. However, the later surgical pathology stated: "This patient's core biopsy showed an unusual IHC positive HER-2 and Her-2 SISH negative." This suggests that both IHC and SISH tests were done on the core biopsy, but that the results were "discordant" or conflicting.

Surgical: ER- and PR-. The IHC was positive (3+). The SISH test was negative.

The documentation received noted the unusual biopsy results, and stated the SISH would be repeated. "This patient's core biopsy showed an unusual IHC positive HER-2 and Her-2 SISH negative. The present IHC Her-2 is positive with strong circumferential membrane staining. The SISH will be repeated on this specimen and will be reported under a different number." [Repeated may mean with respect to biopsy SISH]

It is believed from verbal communication that both tests were each repeated four times (that would be a total of 8 tests on surgical samples). Are you sure your understanding is correct? Sometimes, a different region might be re-tested. Repeating it over and over like that strikes me as unlikely. Please seek clarification.

Based on the above, it seems more likely that in total, four HER2 tests were conducted (not that each test was repeated four times):

(1) Core biopsy IHC: positive

(2) Core biopsy SISH: negative

(3) Surgical specimen: IHC: positive

(4) Surgical specimen: SISH: negative (verbal information only)

It appears that the surgical pathology, confirms what the patient's core biopsy showed: an unusual IHC positive HER-2 and Her-2 SISH negative.

The oncologist stated in a letter: "The HER-2 testing is somewhat more difficult to interpret. ... This therefore would make it uncertain as to the exact HER- status of the patient."

In the US, there are HER2 testing guidelines (ASCO/CAP) that address matters such as test selection, quality of the test lab, interpretation and reporting of results as either "positive", "negative", "equivocal" or "indeterminate". The guidelines also mention "discordant" results in different contexts, including the situation where a patient is "tested with both high quality IHC and FISH and found to have a discordant result between these two tests."

Since you do not have copies of all results, please confirm that (1) no test result was either "equivocal" or "indeterminate". Please confirm that (2) there is no question of other "histopathologic features suggestive of possible HER2 test discordance" based on grade or type (apocrine), or something. Please confirm that "tumor heterogeneity" is excluded as an explanation for conflicting IHC and ISH because of the sampling method. If any of these is not true, the thinking below does not apply.

HER2 status is assigned based on test results, which in this case are reported as "positive" by IHC and as "negative" by SISH. These appear to be "discordant" results. This could be why the oncologist is saying it is uncertain as to the exact HER2-status (positive by one indicator, negative by another indicator). Please confirm it.

You said, "Because of this uncertainty, the oncologist is leaving the decision whether to have chemo followed by Herceptin up to my mom. . .I would have expected that the oncologist would have at least made a recommendation!" Then you said, "As to treatment, he recommended chemo (I think mom said three months) followed by Herceptin."

Please ask if he is "recommending" chemotherapy plus Herceptin because he thinks it is the best treatment option, or if he is saying that given the lack of clarity re HER2 status and available clinical information, it is purely at the patient's option (but see below, regarding ER-PR-.)

Even if outright "recommended", the decision to follow an Oncologist's recommendation is a personal decision, and a patient may choose to decline treatment. The patient must consider the risk/benefit analysis, in light of their personal "risk tolerance. For example, some proceed with a recommended treatment because they wish to do everything possible to reduce risk. Others may feel the magnitude of the benefit is not worth the magnitude of the risk. But if the degree of risk or benefit is not well established, it is harder to decide.

In this regard, the ASCO/CAP guideline document states:

"The literature is lacking evidence on response to HER2- targeted therapy in the subgroup of patients with equivocal results, and there are limited efficacy data in the subgroup tested with both high quality IHC and FISH and found to have a discordant result between these two tests. Patients with such results constitute poorly studied subsets for which there is less confidence in the scores and actual benefit from trastuzumab therapy. Because the retrospective evaluation of the benefit from trastuzumab in patients with apparent discordance between IHC and FISH who were enrolled onto the first generation of trastuzumab trials included only a small number of patients in each of the discordant subsets, patients who would have qualified for enrollment in those trials should be considered for HER2-targeted therapy."

This suggests that patients with both high quality IHC and FISH and found to have a discordant result between these two tests should be considered for HER2-targeted therapy per ASCO/CAP. This appears to be consistent with the Oncologist's recommendation for chemotherapy plus the HER2-targeted therapy of HERCEPTIN. Please confirm that the above text applies to your mother's situation. If you consider any of it in your decision, please confirm the soundness of your reasoning with the Oncologist.

It is possible that because Invasive Apocrine Carcinoma is a relatively rare diagnosis, and because of the uncertainty regarding HER2 status, it may be difficult for the Oncologist to provide very solid numbers estimating benefit from Herceptin. (Even when HER-positive status is clear, small T1b tumors are not very common, and the available studies are limited.) The calculators you used may suffer in the same way. Please confirm all of this.

Herceptin aside, please be sure to give separate consideration to her ER-PR- status (which precludes endocrine therapy) in connection with the possible benefits of chemotherapy. This may factor heavily in why the Oncologist does not support Herceptin alone. Please confirm it.

You mentioned she worries about a heart murmur. These are very common. Please ask the Oncologist if her specific murmur condition is a medically sound reason to decline either chemotherapy or Herceptin.

Would it be possible for you to attend the discussions or conference in by telephone, so you can hear any advice first hand?

With an unusual diagnosis, a person may wish to give serious consideration to seeking a second opinion regarding both the pathology (method, sampling, quality of testing, interpretation of results, whether additional testing is advisable or not) and the treatment advice from an independent institution, from a pathologist and an oncologist. You might receive a different recommendation. Even if generally confirmatory, you may receive more or clearer guidance on the choice(s).

Please obtain at a minimum copies of all test results in written form so you can independently confirm that her results are in accord with what they are saying, and therefore the treatment recommendations based on verbal communication. Trust, but verify.

I realize that they have recommended that your mom commence treatment by Jan 14. If under the current recommendation, the Herceptin is not concurrent with and follows chemotherapy, perhaps she might choose to commence chemotherapy, while at the same time, seek a second opinion review of HER2 test results, and then finalize her decision about Herceptin with the benefit of a second opinion. Please ask the Oncologist if this is a reasonable approach.

Given the unusual case, you may also ask if there is multidisciplinary tumour board at her current institution who would consider the treatment plan.

I will provide some documentation below, but as a priority, please seek clarification and advice directly from her Oncologist.

Best,

BarredOwl

Barred Owl is way over my technical pay grade (haha), but my her was also equivocal, finally after a third level of testing they call amplification they decided I was barely her positive (2.4), and said cautiously to do Herceptin but to monitor. The MO left it up to me. I am doing the Herceptin, but I did it with the thought process being if I had any degradation of heart function I would stop. It is a powerful drug and when it works, it is capable of great things. I know my information may not help, but for me, I felt it was worth doing Herceptin even knowing my oncologist was on the fence. With er and pr negative receptors, without Herceptin, all we have is chemo, unfortunately. I was also a grade 2. Because chemo was recommended for me either way with negative receptors, I could have chosen Taxotere and Cytoxan, or Taxotere, carboplatin and Herceptin. My oncologist is not a fan of Adriamycin in conjunction with Herceptin because of potential heart issues. Since it was recommended that I do chemo either way, I made the decision to do the chemo protocol with Herceptin. Another option was weekly Taxol with Herceptin, which is supposedly an easier chemo to tolerate, but I'm not sure.

How old is your mom? That may factor into the decision making.

Best of luck, there are no easy answers. I feel like I went to the pros, and then they left it up to me to decide.

Something else to consider in the way of testing for Her2 status is to submit a sample for Mammaprint testing.  It is a genetic assay test, but unlike the widely used Oncotype Dx, it is appropriate for those who are Her2+, or suspect they could be.  It would be another piece of info in regards to whether or not to proceed with treatment that includes targeted therapy for Her2+ disease.