Will 30% of Early Stage (1-IIIA) go on to metastasize??

BarredOwl

MammaPrint and BluePrint are two separate tests available from Agendia Inc.

MammaPrint (70-gene test) classifies tumors as either "High Risk" or "Low Risk", and is independent of BluePrint status.

BluePrint (80-gene test) classifies tumors into one of three subtypes: (1) Luminal-type, (2) HER2-type, or (3) Basal-type. With a "Luminal-type" result, the MammaPrint test result (High Risk or Low Risk) can be used to further subdivide "Luminal-type" tumors into Luminal-type (A) or Luminal-type (B).

How does BluePrint work?

As indicated in one of the Sample Diagnostic Reports on-line:

http://www.agendia.com/media/24Feb15_BP-Luminal.pdf

"The BluePrint test result represents the numerical outputs of an 80-gene microarray-based signature that assesses a breast tumor for its molecular subtype by calculating the correlation scores between its gene expression patterns and a template for each of three molecular subtypes (Luminal-type, HER2-type, or Basal-type). Each tumor will have 3 individual scores, and the highlighted molecular subtyping classification of each tumor is determined by the molecular subtype with the highest correlation score."

According to Krijgsman (2010), the assay was developed using this approach:

Krijgsman (2010): "A diagnostic gene profile for molecular subtyping of breast cancer associated with treatment response"

ResearchGate free PDF: https://www.researchgate.net/publication/51545570_A_diagnostic_gene_profile_for_molecular_subtyping_of_breat_cancer_associated_with_treatment_response

(X-out and scroll down to access full pdf)

"Next, a nearest-centroid classification model was built utilizing the 80-gene profile, in a fashion similar to that described previously [15, 24, 25]. Cohort 1a was used to establish a Basal-type centroid profile (based on 28 genes), a Luminal-type profile (based on 58 genes), and a HER2- type profile (based on 4 genes). For all additional samples and for cohort 1a using a leave-one-out CV, a correlation index was calculated between the sample's 80-gene profile and each of the three MSP [Molecular Subtyping Profle] centroids."

Thus, BluePrint uses microarray technology to determine the levels of mRNA expression from 80 genes in a sample from the tumor, and compares the gene expression patterns from the sample with each of three "template profiles" ("MSP centroid profiles"). The comparison is performed using computer-based bioinformatic methods that assess the degree of similarity or correlation between gene expression levels in the sample versus each of the three template profiles (i.e, Luminal-type; HER2-type; Basal-type). The output is three "correlation scores" and the highest score is used to assign BluePrint sub-type.

My layperson understanding is that the degree of correlation with each template profile is reflected by a numerical value or correlation score on a scale of -1.0 to +1.0 as shown on the scale below. Lower values (closer to -1.0) reflect a lower degree of correlation between the sample profile and a particular template, and higher values (closer to +1.0) reflect a higher degree of correlation with the specified template profile.

The following screen shots from sample reports illustrate the selection of the highest correlation score:

In this sample BluePrint report available on-line, the "BluePrint Result" was determined to be "Luminal-type":

http://www.agendia.com/media/24Feb15_BP-Luminal.pdf

The bar with filled blue circle (+0.34) illustrates the highest correlation score among the three correlation scores, (which is also circled in blue at left).

In the case of a Luminal-type result:

"Luminal-type breast cancers can be sub-stratified into "Luminal A" and "Luminal B" using the MammaPrint categorical result of "Low Risk" and "High Risk", respectively, in combination with the BluePrint Luminal molecular subtype."

In other words, the subtype of "Luminal-type" as determined by BluePrint can be further divided into two sub-categories (either Luminal-type (A) or Luminal-type (B)) using the MammaPrint test result risk category:

- If the MammaPrint test result is "Low Risk", then the result is Luminal-type (A).

- If the MammaPrint test result is "High Risk", then the result is Luminal-type (B).

Compare this screen shot from a sample BluePrint report that indicates Basal-type "subtype" (circled at left).

http://www.agendia.com/media/24Feb15_BP-Basal.pdf

The sub-type assigned is the one with the highest "correlation score" of the three scores (i.e., the one closest to + 1.0 on a scale from - 1.0 to + 1.0).

I am a layperson with no medical training and did not receive a BluePrint test. Those receiving this test should confirm all information above with their Medical Oncologist and request a copy of all reports and all associated documentation, along with an explanation of their test results, and related implications for any pending treatment decisions.

BarredOwl

[Edited Sept 2017 to include links to current BluePrint sample reports.]

jojo0529

hello Barredowl,

I appreciate your posts. Believe it or not, the research regarding spread before a Tumor forms in some cases actually was comforting to me. My hope is that my tumor which sat for a long time due to misdiagnosis did not spread. The biggest concerns on my path report were a ki 67 of 25% (despite a miotoc rate of 1) and LVI Indeterminate. My hope is that there was no LVI. If there was I hope it was not widespread. I understand that you are a lay person with no medical training; however, I would like your opinion . Do you think tumors can be present for a long time and not spread?

voraciousreader

jojo..your question has been one that, unfortunately lacks an answer. Researchers toil in their labs trying to discover why one cancer spreads rapidly while another lays dorment for the longest time. My type of cancer, mucinous, usually doesn't spread outside of the breast. In the medical journals, it has been reported, that, there have been mucinous tumors contained in the breast that were as large as 22 cm! Follow up of many years, did NOT see recurrence. Now, for a tumor to grow to 22 cm, it certainly had to be present for quite some time. Likewise, there are patients who have population based screening mammographies that are negative, and some time before their next annual screening, will have a palpable mass that tests positive. That tumor, obviously was either missed on the previous mammo, or was so aggressive, that it wasn't previously there months before. And then you have those patients who have miserable luck who go for their first either population based mammo or diagnostic mammo and are Stage IV. So there you have it, some patients who will have massive tumors that have grown for what seems like a long time and do not spread and then you have others (approximately 15%) who have metastatic cancer from the get go.

Researchers are only now beginning to understand how and why tumors spread. The research is fascinating. I recently read about how healthy and cancer cells communicate with one another. Besides targeted therapy, I think this idea of the communication between the cells is quite interesting because it seems that if, according to the researchers that I have spoken to and read about IF and that is a big IF, we can shut down the communication, then we can possibly stop the spread from occurring in the first place.

https://www.sciencedaily.com/releases/2016/04/1604...

https://www.eurekalert.org/pub_releases/2015-11/fo...

http://news.harvard.edu/gazette/story/2015/12/meta...

Momine

A new study finds that many BC patients OVER-estimate their risk of recurrence:

http://labblog.uofmhealth.org/lab-report/for-breast-cancer-when-does-worry-outweigh-risk

If you read the article, one of the investigators wonders why that is. As an actual patient, that seems like an easy question to answer, and it made me think, once again, that apart from better stats, it would also be great of researchers would actually talk to patients or read BCO at least.

jojo0529

great article. Thank you voracious

BarredOwl

Hi Jojo0529:

VoraciousReader gave excellent examples of how variable different tumors can be with regard to distant recurrence risk. Tumor biology and the local microenvironment--both in the vicinity of the tumor and at distant sites-- appear to affect the escape of cells from the loco-regional area, their ability to travel to and establish themselves at a distant location, persist, and eventually manifest as clinically overt distant metastatic disease.

I explained the nature of the risk of "undetected micrometastatic distant spread" (versus detectable, clinically overt distant metastatic disease) earlier in the thread:

https://community.breastcancer.org/forum/105/topics/812929?page=49#post_4864077

Standard clinico-pathologic features, including tumor histology (e.g., ductal, lobular, metaplastic or mixed, versus more favorable histologies of tubular and mucinous); tumor size; lymph node status; ER, PR, and HER2 status; as well as grade and the presence of lymphovascular invasion have been studied to try to understand how these correlate with distant recurrence risk. They are not perfect as predictors, but based on what is known about the risks presented, these standard features are used to inform treatment decisions about endocrine therapy (for hormone receptor-positive disease), chemotherapy, and/or HER2-targeted therapy (for HER2-positive disease), such that disease with features presenting a greater risk may / will warrant such systemic treatment(s). This body of information is reflected in clinical consensus guidelines regarding systemic treatments.

In addition, the outputs of multiparameter tests, such as OncotypeDX, MammaPrint, Prosigna (PAM50), and EndoPredict, have been studied to understand how the test results (e.g., particular Recurrence Scores) correlate with certain types of recurrence risk, thus providing additional "prognostic" information about recurrence risk that can further inform systemic treatment decisions in appropriately selected patients.

The presence of individual tumor cells in bone marrow (referred to as "Disseminated Tumor cells" (DTCs)) and in peripheral blood (Circulating Tumor Cells (CTCs)) can be detected by immunologic or molecular methods, and these methods are being used to probe questions about distant spread. These techniques use a sample of bone marrow (e.g., from the hip) or blood sample, and thus may be subject to the same types of limitations inherent in any method that relies upon a limited sample of the whole. Research in this area may lead to more reliable prognostic tests in the future, either substituting for or complementing current tools.

Do all invasive tumors shed a few, some, or a lot of cells that can travel to distant sites? I don't really know, but not all such cells are able to establish themselves and cause clinically manifest metastatic disease, either due to host factors (e.g., immune surveillance and killing) and/or systemic therapies. Per Redig (2013) linked below:

"Although [circulating tumor cells] CTCs can be found with reproducible frequency [Note: I am not sure what frequency] in the peripheral blood of patients with breast cancer, results from preclinical studies suggest that the majority of CTCs/DTCs will not form a clinically detectable overt metastasis."

The additional papers linked by VoraciousReader illustrate that we are still learning about what I call "cancer capabilities", including their ability to recruit assistance from other normal cells. A better understanding of the mechanisms of metastasis and colonization at distant sites could lead to improved prognostic markers of distant recurrence risk, as well as improved therapies.

For more reading, see this seminal paper about the hallmarks of cancer:

Hanahan and Weinberg (2011): "Hallmarks of Cancer: The Next Generation"

http://www.cell.com/cell/pdf/S0092-8674(11)00127-9.pdf

Here is the 2013 review article that informed some of my comments above:

Redig (2013): "Breast cancer as a systemic disease: a view of metastasis"

http://onlinelibrary.wiley.com/doi/10.1111/joim.12084/full

(Free PDF available at red PDF button)

BarredOwl

jojo0529

thank you!!!! Very infirmative! I think PR is a protective factor...

stephilosphy00

Hi jojo, I have had my tumor for at least 2 years before it was dx. It has a low ki67 but the grade 3 really makes me worry a lot.

voraciousreader

I don't want to sound silly...but this business of the cancer cells communicating with healthy cells MIGHT lead to an extraordinary breakthrough in treatment. I see it as finding the master key that will lock the door and make it impossible for tumor cells to enter healthy cells homes, thus making metastasis unlikely to occur. Imagine a cancer cell knocking at the door of a healthy cell and the healthy cell answering the intercom and says, "Who is it?" And the cancer cell says, "It's me, your friend and I'm hungry and tired, so will you let me in?" And the healthy cell says, "I know who you are! You are the big bad wolf and I am NOT letting you in! i have a steel door and a stealth lock, so just get lost!" ....

And there you have it! Perhaps the cure for cancer....finally!

Happy New Year dear friends. May we all be well and only have good surprises in 2017!

jojo0529

not silly voracious. It actually makes sense. Steph mine was grade 2 but treated as grade 3 because of ki 67 of 25% . That ki 67 score is great. What was your miotic rate

traveltext

voracious, sort of like tamoxifen:

Tamoxifen is an "anti-estrogen" and works by competing with estrogen to bind to estrogen receptors in breast cancer cells. Tamoxifen is formally known as a selective estrogen receptor modulator (SERM). By blocking estrogen in the breast, tamoxifen helps slow the growth and reproduction of breast cancer cells. Ref

voraciousreader

travel...sort of.. here is some research that suggests tamoxifen and extracellular activity

https://www.ncbi.nlm.nih.gov/pubmed/18996114

.but mosly..i see tamoxifen as ...you are already in the house (inside the cell) and you load up the table with all of your friends (tamoxifen), so when your mother-in-law comes knocking (cancer), you invite her in, but tell her you are sorry, but she can't stay, because there is no room at the table (antiestrogenic). ....another word for this process is intracellular...happening inside the cell

The difference? I think there is some more exciting research where there is a lock on the metal door that, no amount of ringing is going to let that mother in law in! I think if they can shut down the communication between the good and bad cells, you create detente and hence, there is no need to battle. We need to keep the cancer from invading the healthy cells without changing the make up inside of the healthy cell...another word for this is extracellular...outside of the cell.

We will see....

P.S. VR loved her mother in law...no offense intended...

A moderate nderstanding of this promising research..

http://www.sciencedirect.com/science/article/pii/S...

And a few other shorter explanations...

https://www.ncbi.nlm.nih.gov/pubmed/24074795

https://www.ncbi.nlm.nih.gov/pubmed/26743193

https://breast-cancer-research.biomedcentral.com/a...

http://www.sciencedirect.com/science/article/pii/S...

https://www.sciencedaily.com/releases/2016/08/1608...

stephilosphy00

My miotic score was 2, not correlating with the low ki67.

thinkingpositive

where do you find the Miotic score??

mellee

ThinkingPositive, this should be on your pathology report. It's 1 of the 3 factors they use to determine the grade of your tumor. The 2 others are tubules and nuclear pleomorphism.

thinkingpositive

Thanks. I will have to pull it out. I dont recall that being one of the things listed.

thinkingpositive

mellee...found it. Mioti rate3/3. Ki67 was 28%.

lisey

No... Oncotype doesn't show whether you are Luminal A or B. Only the Blueprint / Mammaprint specifies subtype like that

lisey

I'm sure the features of Luminal B are somehow calculated into the scoring - but the oncotype does not confirm whether or not one is Luminal A or B. Some women with high PR+ (Luminal A) still come back with high scores on the oncotype - so you cant say that if you are low score you are luminal A or high score luminal B. In fact, I saw one women with a low PR come back as an 8.

The oncotype and mammaprint use different tools and genetic assay tests to determine risk. I love how the mammaprint actually tests for subtype because we had different plans depending on if I was A or B. (B's do better with AIs than Tamoxifen and they also do better with some chemos).

wallan

Hi there is a lot of discussion going on here, but I m going to put in my two cents.

I was told in 2004 at my first diagnosis, that after all my treatment, I still had a 30% chance of recurrance 15 years out. I had mastectomy, lymph node dissection, AC-T chemo, radiation, tamoxifen (2 years) hysterectomy/oophorectomy and then aromasin for 5 years.It has been 13 years NED until the other day when I was diagnosed with possibly a new primary in the other breast. I am still being assessed.

I still find comfort in the 98% no recurrance stat at 5 years for early stage BC. I agree, this stat may be skewed and misleading don't get me wrong. But I am glad it is skewed in favor of survival for the general non BC public.

Life after breast cancer is not always rosy. Your chance of getting any kind of life insurance is gone. Employers look at you as risk because you may get sick again so it may be difficult to find employment, some friends and acquaintances may treat you like you are still sick etc. There is stigma. I have lived it and you can read in the literature this is a fact.

If the stats leave the impression that early stage BC is "curable" this will reduce that stigma, and women who have had BC will not have as much bias against them. This helps tremendously with fear and panic and the way women are treated once diagnosed. And it does get women to take their breast health seriously and get screened to catch early stage because they have hope it will be "cured". And lets face it, lots of women do NOT have a recurrance ever again because of treatment they get.

I still think your oncologist should tell you your individual risk of recurrance to you so that you can do everything you can to minimize that risk. And I still think women should not be naive and think they are guaranteed cancer free forever after treatment. Life does not work like that. There are lots of diseases that are considered "curable" with drugs or will pass on their own without treatment but can and do come back and sometimes kill you. Influenza, pneumonia are two that come to mind. (I know that BC has more devastating lingering treatment effects than these illnesses, but you get my point).

I think that stating these positive stats gives hope in anotherwise dismal situation.

Just my two cents.......

wallan

thinkingpositive

My question is what does the 30% consist of and I know it probably can't be answered. Is it all grades or grade 3 more so than others or being Her2+, or having positive nodes. OrCan anyone be in that 30%.

Lucy55

ThinkingPostive ...Yes ..I have wondered about that too ..

thinkingpositive

lucy55. I have always been afraid to ask that question and have always thought that there are some that just aren't in that 30%. I go on everyday believing that even with my stats it's possible that I can not be in the 30%. Is that possible??

minustwo

Thinking Positive - I saw another lady post it in reverse and it I thought that was positive. Instead of 30% chance of recurrence, think about 70% chance that there will be no more problems.

traveltext

TP, everyone Stage 3A and below is in the 70% and everyone Stage 3A and below is in the 30%. My BS said that as you approach your five-year NED mark, your chances of long-term survival improve. That's worth holding on to

minustwo

Traveltext - did you mean one of those sentences to say 'above 3A'? Are you stating both as good-news positive numbers? Or as chance of recurrence?

traveltext

Oops, I meant all those below 3A are in both percentage ranges.

marijen

From labblog

One of the reasons for this problem is that there is a lot of propaganda out there that represents breast cancer as a curable disease and makes it seem that if you just get your mammograms on time, it will all be pink balloons and totally fine. Then when women get a diagnosis and start treatment, they discover to their understandable horror that this is not actually true. They discover that conditional survival in BC is flat. They read statistics that 25-30% of patients will eventually develop metastasis. Of course a lot of them freak. We also have serious lacunae in the stats. Long-term survival is not well tracked. Mets are not well tracked. We do not have a database that can tell us how many stage 1 DXs develop mets, and when mets occur, how far out from initial DX. Yet, virtually all BC patients are painfully aware that the standard 5-year benchmark for survival is not reliable in BC.

meow13

marijen, exactly!

dtad

Agreed!