Is a Low Oncotype score for HER2+ Valid to Determine Treatment

Nibaum · February 2016

Hi all,

I am in a very gray area due to the characteristics of my BC. I hope someone can give me some perspective on the Oncotype DX test and a HER2+ diagnosis. I know Oncotype is not usually ordered for HER2+ cases. But in my case, it was ordered because of a grade 1 (with very low mitotic mf count) tumor that is also highly ER/PR Positive (both 100%). The HER2 test thru IHC was 2+ (equivocal), and positive thru FISH on the 2nd reflex test (2.8). ASCO guidelines suggest that such a histologically discordant result be re-tested. My MO missed this suggestion and was ready to start me on TCH just based on the initial HER2+ result. But I am very doubtful of the effectiveness of chemo on such a low grade tumor.

Fortunately, I had a second opinion at an NCI hospital, and that MO recommended I get the pathology reviewed and the FISH re-tested. While I was waiting for the 2nd pathology review, my treating MO ordered an Oncotype DX test for me, mainly to see what the HER2 result would be on the Oncotype DX. My second pathology back two weeks ago and it confirmed the original findings, with a slightly lower positive FISH result at (2.4). But due to delays, my tissue for the Oncotype test was not received until 2/10 and Genomics Health said most cases will take 2 weeks.

Since the 2nd FISH came back positive, I know that I cannot rely on the Oncotype DX test for HER2 status. But based on what gene groupings are used in the Oncotype test, I think I can conceivably still get a low recurrence score even with HER2 amplification if my Ki67 is low. The Ki67 was not determined in my two pathology reports but I know that Oncotype does use Ki67 figure to calculate the recurrence score. But I also know that my chance of getting an Oncotype score under 18 is small. At the same time, I am very doubtful of the effectiveness of chemo on such a low grade tumor.

My dilemma is whether to start Taxol/Herceptin before I get the Oncotype result back. I am just about 8 weeks from surgery so I am anxious to start some kind of systemic treatment. So I scheduled chemo this Friday, 2 /19. My MO did say that I can stop chemo treatment if the Oncotype score comes back low, but I think that is just to placate me. In the meantime, at my request, my MO prescribed me Tamoxifen to take until chemo starts. I think that hormone therapy is more critical for me and was only anxious to start chemo to put me in chemopause.

Since I am on Tamoxifen right now, I can conceivably wait for the Oncotype DX test to come back before I start chemo. But I just don't know if its worth waiting for if a HER2+ trumps a low Oncotype DX score. I just cannot find any literature or even specific cases from members on BCO on how to interpret a low Oncotype RS score with a HER2+ finding. My MO confused me by saying that he would support no chemo if the Oncotype test shows me HER2 negative and a low score. If it's HER2+, he would be reluctant to give me Herceptin without chemo. My thinking is that if the Oncotype test factors my HER2 positive status, a low RS score would be more valid. If so, I would like the option of Herceptin only.

Thanks in advance for any insight or perspective on this.

Nibaum

BarredOwl · February 2016

Nibaum:

Was the Oncotype test ordered by the first MO or the MO from the NCI-designated cancer center?

BarredOwl

gracie22 · February 2016

Hi Nibaum, It's a great question. You may have already researched the threads pretty heavily, but just in case, SpecialK, AlaskaAngel and Barred Owl are resident experts in HER2. AlaskaAngel has offered a great deal of interesting info on using antihormonals/ovarian suppression or ablation + Herceptin for such early stage, node negative cases of highly hormone sensitive BC, rather than the full bore chemo. Agree with you that the Tamox is important now. If you can deal with it, wait for the Oncotype to come back before starting chemo. If it is high, it will give you some peace of mind knowing that you are undertaking the chemo for a good reason. If it's low it will give you something to consider. Assuming the HER2+ diagnosis holds, your oncologist will want to do chemo regardless of Oncotype, but you ultimately decide your own treatment. You seem very clear-eyed about it and will make a call you are comfortable with. I admire your research--and courage in thinking beyond the normal treatment recommendations. My own feeling is that in the future, Oncotype will be used for highly ER/PR+, HER2+ patients to better determine the most effective and patient-friendly treatment.

SpecialK · February 2016

You might consider having a Mammaprint test done. It is a genetic assay test, as is Oncotype, but it is appropriate for Her2+ patients, which Oncotype is not designed for. This test can confirm the Her2 status, and also give you a high or low result while factoring in what your Her2 status is, and there is no intermediate result with this test. Linked below is some info regarding both types of testing, and Her2+ results specifically. Two links reference the same study, but have some additional and/or different info.

While there is a legitimate question regarding whether chemo would be effective on a low grade, more indolent tumor, I think the potential need for targeted therapy could really be the more important question - and is ultimately what would drive decision making. Anyone who is strongly ER+ and Her2+ also faces this dilemma, as chemo is thought to be less effective on strongly ER+ patients. Chemo and targeted therapy for Her2+ is the current standard of care - with differing regimens offered depending on staging info, and my understanding is that Her2 testing trumps Oncotype results. Keep in mind also, that grade is subjective, and tumors are not homogenous - you may have had a higher grade in a different area of the tumor. Do you have the breakdown of your grade score? You can still be grade 1 even with the highest mitotic rate score, so this info might be helpful to know, particularly in the absence of a Ki67%..

http://www.nature.com/bjc/journal/v103/n12/full/6605916a.html

http://onlinelibrary.wiley.com/doi/10.3322/caac.21133/full

http://www.labtestconsult.com/absent-gold-standard-for-her2-testing-researchers-question-role-of-oncotype-dx-beyond-ihcfish/

Nibaum · February 2016

BarredOwl - The Oncotype DX test was ordered by the my first & treating MO, who is a generalist. The NCI doctor is a BC specialist. I told my treating MO that I was paying out of pocket for the 2nd FISH test with the NCI center because I didn't want to deal with insurance and more delays. I did ask him to have my original lab retest it too through insurance just as a triple check. Instead, he decided to order an Oncotype DX test to have an alternate Her2 assay and perhaps in case the 2nd FISH test came back HER2 negative. I think my insurance approved it because my tumor size was only 1 cm.

Special K - On both my first pathology and 2nd pathology, the overall grade was 1. On the first it was 4/9 (1 nuclear grade, 2 tubular formation, 1 mitotic index). The 2nd NCI pathologist (who is a very experienced) scored it 5/9 (2 nuclear grade, 2 tubular shape, 1 mitotic index). But the 2nd pathology review had more details on the mitotic index, with a 0 mf/ 10 hpf, which I think is as low as it can go. I realize that another part of the tumor may show something else but it made me doubt chemo even more. So at least the Oncotype DX will factor in Ki67, which is another proliferation marker. Genomics Health said they won't give the Ki67 separately in my report. But if I get a low RS score, then I would know my Ki67 was on the low end. If my RS score is mid to high, then the Ki67 was likely on the higher end.

As for the Mammaprint test, I guess the timeframe to get it done seems to be too late. Plus my insurance won't cover it, so its $5000 out of pocket, which is cost prohibitive for me at this point. And if the Oncotype score comes back intermediate or high, then chemo/Herceptin is pretty much a given. Its only if the Oncotype score comes back low that I will have be faced with a real dilemma.

Thank you for helping me understand this conundrum!

SpecialK · February 2016

Will be keeping fingers crossed that the Oncotype, with inherent Ki67 info, offers you definitive answers. Wishing you the best, please keep us posted on the upcoming info

ShetlandPony · February 2016

Here is a thread discussing Ki67 and Oncotype. Surprisingly, some people had high Ki67 and a low Oncotype score and/or low mitotic rate. Is it possible to have your Ki67 done separately at this point?

https://community.breastcancer.org/forum/147/topic...

BarredOwl · February 2016

Hi Nibaum:

I am a layperson with no medical training.

I would have some concern that the first MO, who is not a specialist, is not very familiar with the Oncotype test for invasive disease, including eligibility requirements and guidelines regarding its use in particular patient subsets and/or clinically validated uses of the multi-gene Recurrence Score, or with the limitations of the individual HER2 score.

The articles posted by SpecialK illustrate some controversy surrounding and possible deficiencies in the use of the individual HER2 score, which is derived from measurement of mRNA levels of many cells, and not of protein (IHC) or DNA (FISH). I do not believe that the HER2 result should be used to contravene HER2 status determined by FISH. Please consult with the MO from the NCI-designated cancer center about any proposed use of the Oncotype HER2 score in your decision-making, as there has been concern that it may underestimate HER2 leading to undertreatment.

To my knowledge, HER2-positive patients are not eligible for the Oncotype test for invasive disease:

http://breast-cancer.oncotypedx.com/en-US/Professi...

OncotypeDX is a kind of biomarker test. In Oncotype for invasive disease, the biomarker is the gene expression pattern/profile of mRNA levels from 16 cancer-related genes (5 controls)). The mRNA expression data is used to compute a Recurrence Score, which is used to predict adjuvant therapy benefit and 10-year risk of distant recurrence.

Very generally, biomarker tests like this are indicated for use in patients who share important clinical features with the patient populations represented in the studies used to design the test and used to establish the prognostic and predictive value of the test. The test has no proven prognostic or predictive value in other types of patients. In other words, if the test is not "validated" in other types of patients, it cannot be safely used to guide clinical decisions for those other patients.

The scope of validation is reflected in "eligibility". In general, if a person is not "eligible" for a commercial biomarker test, it may reflect that the test either was never tested in such patients or not tested adequately in such patients, did not work as intended in such patients, or is still being tested in such patients (and may not work).

The fact that HER2-positive patients are not eligible for the test likely reflects that the test is not or is not sufficiently validated in HER2-positive patients, and hence lacks prognostic or predictive value in HER2-positive patients. Similarly, consensus guidelines from the NCCN (Version 1.2016) do not include the use of the test for HER2-positive patients, but only in certain hormone-receptor positive, HER2-negative patients.

I strongly recommend that you discuss with the expert MO from the NCI-designated cancer center the use and quality of validation of the Oncotype test in HER2-positive patients in general, and the proposed use of the Recurrence Score in your particular case. I have concerns that it may not be appropriate.

BarredOwl

ChiSandy · February 2016

This begs the question: have there been any studies (even retrospective & anecdotal) on triple-positive tumors that are highly ER+ as to just how aggressive they are? Or whether HER2 overexpression negates the slower cell division characteristic of highly ER+ grade 2 or lower tumor cells? Why hasn’t there been any genomic assay developed for the triple-positive cohort of patients to give them a recurrence-score and chemo-effectiveness benchmark as dependable as OncotypeDX is for early Luminal A (ER+/PR+/HER2-, grade 2 or lower) node-negative breast tumors? Has anyone studied the effectiveness of Herceptin and hormonal therapy given without cytotoxic chemo? Is it a matter of nobody--patients or doctors--being willing to roll those dice?

BarredOwl · February 2016

Nibaum:

The power went out in the middle of editing my post above. Please note in the bold text in the third paragraph.

BarredOwl

Meow13 · February 2016

Symphony test, 3 separate test. I think one is mammoprint this is for everyone regards of her2 and hormone status. See if your mo can order it.

Nibaum · February 2016

ShetlandPony - The 3 MOs that I have seen said that Ki67 score is not consistently replicable so they do not use it. So I am unlikely to get an MO in my area to order it separately. I will at least get it indirectly thru the Oncotype DX score. With a HER2 +, a high Ki67 score will surely push me into the intermediate/high range.

BarredOwl - My sense is that NCI MO does not think the Oncotype DX is valid for HER2+. After my second FISH came back positive, she immediately recommended Taxol/Herceptin as the treatment even though she knew that I was still waiting for the Oncotype result. When I asked her if my Grade 1 and highly HR+ tumor warranted a lighter chemo, such as Navelbine, she pointed out that 10% of patients of the 400 patients in the Taxol/Herceptin study by Dana Farber had grade 1 tumors. I was very discouraged because my treating MO is even more conservative and by the book (i.e. NCNN guidelines). The DF study did not specify the size or the ER/PR status of those with grade 1 tumors.

Thank you! You put into words my vague concern that I can't even use a low Oncotype score to forgo chemo, even if my MO was willing to treat me with Herceptin only. I am hoping the results for the phase 2 Herceptin only trial for those over age 65 will come out soon. At the very least, if I am struggling with Taxol, my MO and I can have some assurance that Herceptin only is still helpful. I have Thalassemia (anemia) and Raynauds syndrome on my right hand. So I may not be able to get my red blood cells back up and may be more prone to neruopathy. Otherwise I have no other known health issues that would contraindicate chemo.

Although I read Aetna's guidelines for Oncotype DX, which state that only HER2+ tumors that are 1 cm or less would be covered. Aetna is pretty conservative in what tests they consider medically necessary so there must be some precedent for the Oncotype DX test for early HER2+ cases. Aetna considers Mammaprint and all other genetic assays experimental since they are not in the NCNN guidelines.

So my thinking now is to proceed with the weekly Taxol/Herceptin treatment and if my Oncotype score comes back low, I may have to pay for a Mammaprint on my own if I want a clearer picture of my risk.

I really appreciate everyone's input!

BarredOwl · February 2016

Nibaum:

[EDITED line 1 to insert " / insufficient'] For the reasons noted above (lack of / insufficient validation in HER2-positive patients), I would also be concerned about using the multi-gene Recurrence Score (generated by a test that is not indicated for use in HER2-positive patients) to extrapolate an estimated Ki-67 value in a HER2-positive patient. Please consult with the MO from the NCI-designated cancer center about this, and inquire whether the approach is sound or not. I suspect it is not.

There is some reported correlation between Recurrence Score and Ki-67, such as this 2011 report in HER2-negative patients:

http://www.nature.com/bjc/journal/v105/n9/full/bjc...

I do not know if there are any subsequent studies that either confirm or undermine these findings. In any event, as Shetlandpony pointed out, there are members here whose Recurrence Scores were not consistent with actual Ki-67 values. In addition, as a HER2-positive patient, it is critical to note that all 53 cases analyzed in the paper were T1–2 N0 M0 (ER/PR-positive, HER-2-negative), and the results provide no information as to whether such a correlation can be found in HER2-positive patients.

Regarding requesting Ki-67 immunohistochemistry (IHC) testing, like yours, some institutions no longer conduct Ki-67 testing (e.g., one recent experience from someone seen at Dana Farber in MA). Apparently, there may be methodological issues with the immunohistochemical (IHC) methods used to provide a semiquantitative estimate of the percentage of nuclei with positive Ki-67 protein staining. For example, the authors of this paper (cited solely for the method information) discuss the problem of "interobserver variability", which can result in different test results when different pathologists examine the same sample, or even when the same pathologist repeats the test:

http://www.nature.com/labinvest/journal/v94/n1/ful...

"Ki-67, a marker of cell proliferation, is expressed in all phases of the cell cycle, except G0. This protein is localized to the nucleus and its expression is often quantified in terms of percentage of positive nuclei. This is usually a semiquantitative estimate determined by pathologists who count as many as 1000 nuclei to determine this proportion. The threshold for differentiating high and low Ki-67 reported by the literature varies widely from 1% to 28.6%. Another potential source of variability in this measurement is the field of view (FOV) selected by the pathologist for determining Ki-67. It is controversial whether the pathologist should choose hotspot areas or simply count all areas and average."

. . . [Our new] method is most importantly objective, and therefore avoids some of the pitfalls of subjective analysis of percent positive nuclei, including interobserver variability and determination of a cut point between high and low expression. This method also enables efficient analysis of the entire biopsy, removing the subjectivity of hotspot selection. Averaging all FOVs also trended toward a marginally more sensitive and specific assay than considering only the maximum FOV."

Lack of reproducibility would tend to undermine any prognostic value.

I note that there also appears to be variation or concerns with the "cut-off" threshold to determine "high" or "low", and some possible lack of clarity around the prognostic significance of Ki-67 determined by IHC in some sub-groups.

http://www.nature.com/labinvest/journal/v94/n1/ful...

http://link.springer.com/article/10.1007/s10549-01...

http://www.nature.com/nrclinonc/journal/v12/n5/ful...

I was not aware that Ki-67 was a commonly considered factor in the HER2-positive setting. Please ask the MO from the NCI-designated cancer center whether Ki-67 IHC testing is reproducible and prognostic in HER2-positive patients, and whether it can provide information of value or not.

You also mentioned that at your request, "my MO prescribed me Tamoxifen to take until chemo starts." I note that the NCCN guidelines for breast cancer indicate that: "Chemotherapy and endocrine therapy used as adjuvant therapy should be given sequentially with endocrine therapy following chemotherapy." As soon as possible, please inform the MO at the NCI-designated cancer center that you have commenced endocrine therapy. Please request his recommendation re (a) when to stop endocrine therapy relative to commencing chemotherapy; and (b) when to re-start endocrine therapy later on.

I have highlighted a number of areas of specific inquiry with the MO at the NCI-designated cancer center, but please confirm any information provided if used in your thinking.

BarredOwl

Nibaum · February 2016

ChiSandy - It was this article about triple positive tumors had me start questioning the one size fits all treatment for HER2+ cases, esp. when I had such a low grade tumor: http://www.sciencedirect.com/science/article/pii/S0305737214002102 Its not a study per se but more of an analysis and indirect conclusions drawn from various studies of HER2 positive breast cancers. Its a long article and there clinical concepts that I did not fully understand. But the gist was that triple positives, especially those that are highly ER/PR positive have a very similar prognosis to those who are ER/PR positive/HER2 negative, and are more likely to be over treated. In the Neoadjuvant Setting section, there's a very interesting discussion of why those with triple positive tumors have consistently lower PCRs than those who are HR-/HER2+. It even cited a study that used dual HER2 blockades without chemo and gave those who are HR+ an AI (endocrine therapy) and this resulted in higher PCR rates for the triple positives. The authors of the article draw the conclusion that adding hormone therapy concurrently with the HER2 targeted therapy may be the way to treat triple positives in the neo-adjuvant settings. But can we take it one step further and speculate that this would also apply in the adjuvant settings, but it would be difficult to do such studies due to the high risks involved. Perhaps the results for this Herceptin only trial https://clinicaltrials.gov/ct2/show/NCT00796978 could shed some light on the differences between HR+ and HR- cohorts.

If you are interested, the article cited this study which discusses the differences between HR- and HR+ in HER2 positive BC:

https://www.researchgate.net/publication/262265734_Two_histopathologically_different_diseases_Hormone_receptor-positive_and_hormone_receptor-negative_tumors_in_HER2-positive_breast_cancer

It found a correlation between HR+ and lower grade and less aggressive tumors. I guess I am frustrated that we are not at the point that we can use this information to guide treatment yet. But I think future triple positive BC survivors will eventually get the appropriate level of treatment.

Nibaum · February 2016

BarredOwl - Thank you for your additional input. The NCI MO told me that they do not use Ki67 for any BC cases and did not specifically rule it out for HER2+. Exactly as you said, she said it is not reproducible and should not be used to undermine/overturn the mitotic index. It was actually the NCI MO's nurse practioner who suggested that I get hormone therapy if there will be a delay in my chemo/Herceptin treatment. But I will ask the NCI MO specifically tomorrow now that I am actually taking Tamoxifen. I started taking last Friday (4 days ago) thinking that I may wait until the Oncotype score comes back before starting chemo or not. So now that I am more settled on starting chemo this Friday, I will probably stop now to be on the safe side. My treating MO said to stop Tamoxifen before the day of chemo.

As for finding another MO that specializes in BC, I have very limited choices in my HMO IPA group. My oncology surgeon and PS are great and if I switch now IPAs now, I would have to find a new BS and PS. I am 8 weeks out, so switching MOs now would delay treatment even further. Plus to be fair, I think my case is a little unusual and even the NCI MO did not really address the particulars of my BC when she made her treatment recommendations. My MO only ordered an Oncotype Test as a one off, and he was going to proceed with treatment without the result. It was me that latched onto the Oncotype test as something I could use.

It was the 3 weeks between my surgery and the second opinion consult with NCI MO that pushed everything back. Initially, my case seems pretty straightforward and TCH was going to be my treatment plan. Perhaps my treating MO should have questioned the initial HER2 result, promptly ordered a 2nd FISH test for confirmation and I wouldn't be under this time constraint.

I will re-read your post more carefully and read the links you provided. Thank you!

BarredOwl · February 2016

Hi Nibaum:

I actually edited that last post to delete the last paragraph before reading your reply.

I note your comment re the Aetna policy. I am surprised, because it is my layperson's understanding that NCCN guidelines do not provide for Oncotype in HER2-positive patients (Version 1.2016). Please expressly confirm this with your providers.

The version of the policy (Number: 0352) that I see on-line tonight lists five requirements which must all be met ("where all of the following criteria are met") to satisfy "medical necessity". I am not sure I am reading the right document or not. I may not be understanding it either.

The third criterion says "less than 1 cm in diameter", which is different from what you quote above.

Your local oncologist's "advice" appears to reflect the fifth criterion in the event of a "low" score. Do you have a choice to elect treatment even if the score is low?

Please check the exact language of your current policy in all respects, print it out, discuss it with your MOs to confirm whether the test was ordered on this basis or not, if so what does it mean, what options are available to you, and what the implications for payment are (for the test and for treatment), should you choose to proceed with treatment but get a low score.

I am just a fellow patient, with no medical training. There may be errors in the information I have provided in this thread. Please be certain to confirm any and all information from me with an expert medical oncologist to ensure current, accurate case-specific expert professional advice and sound decision-making.

BarredOwl

kcat2013 · February 2016

Nibaum, others on this thread have given you lots of good info but I thought I'd throw in my experience as additional food for thought.

I'm someone who is Her2 positive but also had an oncotype done. Ki67 was 62. My initial Her2 test was equivocal so that got sent off for FISH and in the meantime my MO also ordered oncotype. I got the oncotype results back before the FISH. Oncotype was 54. FISH then came back positive. Interestingly, oncotype said I was Her2 negative, but my MO said FISH trumped that. Even though the oncotype should not be used in treatment decisions for Her2 positive patients, in my case it provided a bit more info for us--info that made it clear that chemo and herceptin were good choices for me even though I had a very small tumor.

As barredowl pointed out, the oncotype test should not be used to determine Her2 status. So I would be leary of following your 1st MO's advice using the oncotype as a guide on that. Good luck in your decision making.

BarredOwl · February 2016

Hi Nibaum:

Thanks for the links.

I found this new ASCO guideline (2016) this evening, which is at least consistent with NCCN guidelines in not recommending Oncotype for HER2-positive invasive disease:

"Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline"

http://jco.ascopubs.org/content/early/2016/02/05/J...

It does not really support much at all. See e.g., MammaPrint.

BarredOwl

Nibaum · February 2016

BarredOwl - I did read on the Aetna bulletin that it was less than 1 cm so I didn't think the Oncotype test was going to be authorized by my IPA. But when it was approved, I just thought that 1 cm was close enough (or it was the actual intent) since NCNN guidelines use the less than or equal to 1 cm as the cutoff for various groupings. I also read the part about the low score and forgoing chemo treatment. But right after the Oncotype test was approved, I was also approved for the Taxol/Herceptin regimen. But I will check with my MO (and maybe AETNA) about the ramifications of a low score. I certainly did not agree to no treatment as a condition of getting the test since I wasn't consulted when the test was ordered. I found out after the fact.

SpecialK · February 2016

nibaum - adjuvent administration of targeted therapy and anti-hormonal therapy does occur now as standard of care since you begin anti-hormonals concurrently with the continuation of Herceptin only infusions once you are finished with the chemo/targeted therapy portion of systemic treatment, although this is not in lieu of chemo/targeted therapy. I had 6 TCH over the course of 15 weeks, began anti-hormonals 4 weeks later, concurrently with continued Herceptin, for 33 additional weeks - so, roughly double the time. I realize you were referring to the article regarding this, but wanted to point this out because often the focus is on chemo/targeted therapy and one doesn't look beyond that and see that you actually spend a longer time period on targeted therapy and anti-hormonals than you do on chemo.

BarredOwl · February 2016

Hi Nibaum:

I would like to clarify my remarks. The fact that HER2-positive patients are not formally eligible for the Oncotype test for invasive disease likely reflects that the test is not sufficiently validated in HER2-positive patients, and hence may lack prognostic or predictive value in HER2-positive patients. That is my layperson's view.

Consistently, consensus guidelines from the NCCN (Version 1.2016) as of this date, do not include the use of the Oncotype test for HER2-positive patients, but only for certain hormone-receptor positive, HER2-negative patients. That is my layperson's understanding.

However, I am a layperson with no medical training. I may be unaware of specialized information. Therefore, this information should be confirmed with your medical oncologists, to ensure that you receive accurate, current, case-specific expert medical advice from qualified medical oncologists regarding such testing in your particular case.

Please inquire with your medical oncologists specifically whether current clinical practice guidelines for breast cancer provide for the use of the Oncotype test in your specific case or not. If the Recurrence Score is to be relied upon in any way, please also request an explanation of the quality and scope of validation of the Oncotype test in HER2-positive patients in general and in respect of HER2-positive tumors of the same size as yours, and whether any such evidence that is available is sufficiently robust to rely on for decision-making purposes in your particular case.

BarredOwl

Nibaum · February 2016

Hi BarredOwl,

I understand your concerns about OncotypeDX and HER2+. And thank you for the 2016 ASCO guidelines on biomarkers. There doesn't seem to be any tools (at least in the ASCO guidelines) to help guide treatment for "seemingly" low risk HER2+ BC. I'll have to think long and hard whether its worth the out of pocket cost for a mammaprint if there's no consensus in the US on its use for any BC, let alone HER2+ BC. If I had a grade 2 or 3 tumor that is not highly ER/PR positive, I would not be questioning the standard Herceptin based treatment (or at least not as much).

Even Herceptin.com states that its for early BC in these situations: If it has not spread into the lymph nodes, the cancer needs to be estrogen receptor/progesterone receptor (ER/PR)-negative or have one high risk feature.*...*High risk is defined as ER/PR-positive with one of the following features: tumor size >2 cm, age <35 years, or tumor grade 2 or 3.

Not that I am not even thinking of foregoing Herceptin based treatment, but was hoping I could get it with a lighter non-taxane chemo. Unfortunately, we are just not there yet with more target therapies.

Sorry for the pity party Sad ! I do feel fortunate that I can even explore the idea of less treatment! Smile

BarredOwl · February 2016

Hi Nibaum:

These decisions have an uncomfortable amount of judgment and uncertainty in outcome. Please feel free to complain.

If you are wondering about MammaPrint, do not hesitate to ask your MOs for their views of the recommendations and remarks in the ASCO document and the potential utility of the test in your specific case.

The distinctions made in the ASCO document about MammaPrint seem nuanced and the brief explanations densely packed. It assumes a high level of understanding of the test outputs and underlying research, which we do not have.

I also do not know how "Type", "Evidence quality", and "Strength of recommendation" would be understood by specialists with relevant clinical experience with the test and its use.

The disclaimer from the ASCO guideline should be read:

"Guideline Disclaimer

The clinical practice guidelines and other guidance published herein are provided by ASCO to assist providers in clinical decision making. The information herein should not be relied on as complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and the time it is published or read. The information is not continuously updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified herein and is not applicable to other interventions, diseases, or stages of disease. This information does not mandate any particular course of medical care. Furthermore, the information is not intended to substitute for the independent professional judgment of the treating provider because it does not account for individual variation among patients. Recommendations reflect high, moderate, or low confidence in the net effect of a given course of action. The use of such words as must, must not, should, and should not indicates that a course of action is recommended or not recommended for either most or many patients, but latitude exists for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. ASCO provides this information on an as-is basis and makes no warranty, express or implied, with regard to the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property that arises out of or are related to any use of this information or for any errors or omissions."

I send you positive energy as you seek additional information towards coming to a decision about what is best for you.

BarredOwl

Meow13 · February 2016

http:www.knowyourbreastcancer.com/symphony-test

It says anyone who has invasive breast cancer is eligible. If I have a reoccurrence I will ask for it.

Tresjoli2 · February 2016

hmmm...how did I end up with grade 3 Cancer that is both 100%,ER/PR positive AND hugely over expressing Her2. (FISH ratio of 4.8)?I didn't realize that was unusual, but looks like maybe it is?

SpecialK · February 2016

tresjoli - same for me - 96% ER+, Her2+++, I don't think we are unusual, if you survey the TP thread many of us fit those criteria.

BarredOwl · February 2016

Hi Meow13:

Regarding MammaPrint, I note that the patient-oriented "Symphony" site is intended to encourage patients to appropriately inquire with their MO regarding their eligibility for the test.

For information only and subject to confirmation with one's medical oncologist, the professional site from Agendia includes more specific eligibility requirements, and it appears that not everyone may be eligible. The information below also appears to be consistent with the Physician's Brochure applicable to the United States.

http://www.agendia.com/healthcare-professionals/br...

"Mammaprint" (fresh tissue) and "MammaPrint FFPE" tests are indicated for breast cancer patients that fulfill the following criteria:

Breast Cancer Stage 1 or Stage 2
Invasive carcinoma (infiltrating carcinoma)
Tumor size ≤5.0 cm
Lymph node negative
Estrogen receptor positive (ER+) or Estrogen receptor negative (ER-)
HER2/neu: negative or positive
Women of all ages

The above reflect FDA requirements and it is possible that eligibility differed in the past for the Laboratory Developed Test. It is also possible that clinical practice may differ somewhat in scope (e.g., may be broader) from specific FDA requirements.

Regardless of the above, any patient interested in the MammaPrint test should always consult their Medical Oncologist regarding their potential eligibility and suitability for the test, to ensure receipt of accurate, current, case-specific information and expert professional advice regarding eligibility (which may change over time).

BarredOwl

MaggieCat · February 2016

Was reading this thread yesterday and then today I get an e-mail about the new ASCO guidelines.... "To provide recommendations on appropriate use of breast tumor biomarker assay results to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer."

Clinical interpretation of literature review.

MammaPrint has prognostic value in HER2-positive breast cancer.³¹ However, the panel does not consider a 10-year distant DFS of 84%³¹ sufficiently favorable to omit chemotherapy from an adjuvant regimen and concluded that the data do not support use of the 70-gene assay to decide whether a patient with HER2-positive breast cancer should receive adjuvant chemotherapy.

http://jco.ascopubs.org/content/early/2016/02/05/JCO.2015.65.2289.full

Nibaum · February 2016

Barred Owl - As expected, the NCI MO told me that Oncotype DX is not validated for Her2+ BC and she does not recommend taking Tamoxifen prior to chemotherapy. My treating MO would not have used the Oncotype DX result either, unless I really insisted and refused chemo treatment. It was never my intent to forego Herceptin based treatment. BC, esp. HER2+, is very serious and I am grateful that I have the benefit of this targeted therapy.

I was just exploring the idea of how to define a lower risk HER2+ bc that would warrant less treatment. Thank you for everyone's input. You all helped me confirm what I already knew deep down, that there is just not enough information to go against my doctors' recommendations. I am just not brave (or foolish?) enough.

So I am starting my first Taxol/Herceptin treatment this Friday with a much better frame of mind. I will report back what my Oncotype DX score is when I get it.

Thanks again!

BarredOwl · February 2016

Hi Nibaum:

It is good to have that expert advice as part of your due diligence. I will keep you in mind this Friday, and will be hoping you tolerate treatment very well.

BarredOwl

Nibaum · February 2016

I actually got my Oncotype score today - 19. I am actually happy with this number. If it was much less, I may be tempted to second guess my treatment. I know that some HER 2 negative bc patients struggle with whether to do chemo or not with 19. I am glad its not much higher too. I get some psychological comfort that perhaps the low mitotic rate does reduce my recurrence risk, even if Oncotype DX is not validated for HER2+.

But according to the front desk staff, my MO's office only got the first page of 3 pages from Genomics Health today. So the only numbers I know so far is the RS of 19 and that my 10 year risk of distant recurrence is 12% on Tamoxifen alone. Presumbably pages 2 and 3 will give what it would be with chemotherapy and the breakout for ER, PR, and HER2. Hopefully, they will be at my MO's office tomorrow when I go for my first treatment.

So more to satisfy my curiosity and not to change my treatment plan, I will look into whether its worth getting a mammaprint, which is not covered under my insurance.

Nibaum

Is a Low Oncotype score for HER2+ Valid to Determine Treatment

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