Mammaprint Low Risk - is running Blueprint necessary?

Hi mellee:

I have no opinion on whether you should seek further testing or not. However, while it is quite likely, it does not appear to be true that HER2-negative status by standard pathology necessarily means that BluePrint subtype will not be HER2-type. Note that per Krijgsman (2010), the "HER2-type centroid profile" used in the BluePrint test includes mRNA levels from four genes. (HER2 status by standard pathology methods assesses gene amplification of a single gene ERBB2 (also known as HER2/neu) (by FISH) or overexpression of HER2 protein from a single gene (by IHC).)

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 the dialog box and scroll down to 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)."

This 2014 study reports IHC-determined statuses versus BluePrint subtype:

Whitworth (2014): "Chemosensitivity Predicted by BluePrint 80-Gene Functional Subtype and MammaPrint in the Prospective Neoadjuvant Breast Registry Symphony Trial (NBRST)"

http://link.springer.com/article/10.1245%2Fs10434-014-3908-y

A free PDF is available for downloading.

Regarding standard pathological assessments:

"Hormone receptor (HR) status (ER and PR) and HER2 status were determined locally on pretreatment core biopsies [as this study was in the neoadjuvant setting]. Both ER and PR status were determined by IHC and were considered positive if there was [greater than or equal to] 1 % positive staining. HER2 status was determined by IHC and/or FISH assays locally. HER2 status was regarded as positive if there was 3+ staining and/or FISH positivity."

As shown in Table 2, two (2) tumors that were deemed hormone receptor-positive (HR+) and HER2-negative by IHC/FISH were assigned the HER2-type subtype by BluePrint (see line 1):

Specifically, they found that "37 of 211 (18 %) IHC/FISH luminal (HR+/ HER2-) patients were not BPLuminal (35 BPBasal and 2 BPHER2)." Note that 35 out of 211 (16.6% by my calculation) of HR+/ HER2- tumors by standard pathology were assigned to the Basal-type subtype by BluePrint. Note the 1% positive staining threshold used for ER and PR status.

Regarding the subtypes of MammaPrint "Low Risk" tumors, if I am reading it correctly, per the last line of Table 1 (below), out of 365 MammaPrint "High Risk" tumors, none (0) were classified as Luminal-type A according to BluePrint. (This is wholly expected, since the MammaPrint "High Risk" category is used to categorize BluePrint Luminal-type tumors as Luminal-type (B), while the MammaPrint risk category of "Low Risk" is used to categorize BluePrint Luminal-type tumors as Luminal-type (A).) Per the second-to-last line of Table 1, out of 61 MammaPrint "Low Risk" tumors, 59 (96.7%) were BluePrint "Luminal-type A" and 2 (3.3%) were BluePrint "HER2-type". The sample size is not huge, so the percentages might differ somewhat if a larger cohort was examined.

You may wish to inquire with Agendia and your Medical Oncologist whether there are any additional published studies that speak to your question.

As far as being "certain" about Luminal A or Luminal B status, unfortunately certainty cannot be achieved. Different multiparameter gene expression profiling tests (e.g., BluePrint, PAM50) use different gene sets to approximate the "intrinsic subtypes" originally defined by Perou in 2000 (using a different methodology). Krijgsman (2010) cited above includes this figure illustrating the overlap of different gene sets:

Not surprisingly, when compared head to head, these subtyping tests are not fully concordant with each other. Thus, for example, it would seem more accurate to say "the tumor was classified as Luminal-type A by BluePrint/MammaPrint" than it would be to say "the tumor is Luminal A".

I am a layperson with no medical training. All information above should be confirmed with a medical oncologist to ensure receipt of accurate, current, case-specific expert medical professional advice.

BarredOwl