Luminal B vs. HER-2 enriched?

[bejuce]

Have you all seen the NYT and Nature articles on the 4 subtypes of breast cancer? It seems that they're classifying HER-2 enriched as ER-/PR-/HER-2+ and Luminal B as ER+ and/or PR+ and HER-2+.

I have not yet read the Nature article, but I'm wondering if there was any talk of prognosis differences between Luminal B and HER-2 enriched. Also, the Susan G. Komen website talks about this classification and says that HER-2 enriched benefits from Herceptin but they don't say that Luminal B benefits from it. Are Luminal B tumors usually not as responsive to Herceptin? Or is that something that the researchers are still working on to determine for sure? Lani, if you're reading this, can you please provide your insightful comments on the differences between Luminal B and HER-2 enriched?

Thanks!

[Laurel]

Good question, Marcia.

[Mandamoo]

Good question. I am finding a lot of this new research confusing. I am ER and pr negative and definitely not a great responder to herceptin progressing while in adjuvant therapy. I was always led to believe that hormone negative disease both triple neg and her2pos is the much nastier variant?
Interested in insights here too.

[Lani]

haven't had a moment to respond, but will try to soon

[Lani]

DNA amplification of HER2 was readily evident in this study (Supplementary Fig. 9) together with overexpression of multiple HER2-amplicon-associated genes that in part define the HER2E mRNA subtype (Supplementary Fig. 5). However, not all clinically HER2+ tumours are of the HER2E mRNA subtype, and not all tumours in the HER2E mRNA subtype are clinically HER2+. Integrated analysis of the RPPA and mRNA data clearly identified a HER2+ group (Supplementary Fig. 12). When the HER2+ protein and HER2E mRNA subtypes overlapped, a strong signal of EGFR, pEGFR, HER2 and pHER2 was observed. However, only ~50% of clinically HER2+ tumours fall into this HER2E-mRNA-subtype/HER2-protein group, the rest of the clinically HER2+ tumours were observed predominantly in the luminal mRNA subtypes.

These data indicate that there exist at least two types of clinically defined HER2+ tumours. To identify differences between these groups, a supervised gene expression analysis comparing 36 HER2E-mRNA-subtype/HER2+ versus 31 luminal-mRNA-subtype/HER2+ tumours was performed and identified 302 differentially expressed genes (q-value = 0%) (Supplementary Fig. 18 and Supplementary Table 7). These genes largely track with ER status but also indicated that HER2E-mRNA-subtype/HER2+ tumours showed significantly higher expression of a number of RTKs including FGFR4, EGFR, HER2 itself, as well as genes within the HER2 amplicon (including GRB7). Conversely, the luminal-mRNA-subtype/HER2+ tumours showed higher expression of the luminal cluster of genes including GATA3, BCL2 and ESR1. Further support for two types of clinically defined HER2+ disease was evident in the somatic mutation data supervised by either mRNA subtype or ER status; TP53 mutations were significantly enriched in HER2E or ER-negative tumours whereas GATA3 mutations were only observed in luminal subtypes or ER+ tumours.

Analysis of the RPPA data according to mRNA subtype identified 36 differentially expressed proteins (q-value <5%) (Supplementary Fig. 18G and Supplementary Table 8). The EGFR/pEGFR/HER2/pHER2 signal was again observed and present within the HER2E-mRNA-subtype/HER2+ tumours, as was high pSRC and pS6; conversely, many protein markers of luminal cancers again distinguished the luminal-mRNA-subtype/HER2+ tumours. Given the importance of clinical HER2 status, a more focused analysis was performed based on the RPPA-defined protein expression of HER2 (Supplementary Fig. 19)—the results strongly recapitulated findings from the RPPA and mRNA subtypes including a high correlation between HER2 clinical status, HER2 protein by RPPA, pHER2, EGFR and pEGFR. These multiple signatures, namely HER2E mRNA subtype, HER2 amplicon genes by mRNA expression, and RPPA EGFR/pEGFR/HER2/pHER2 signature, ultimately identify at least two groups/subtypes within clinically HER2+ tumours (Table 1). These signatures represent breast cancer biomarker(s) that could potentially predict response to anti-HER2 targeted therapies.

Many therapeutic advances have been made for clinically HER2+ disease. This study has identified additional somatic mutations that represent potential therapeutic targets within this group, including a high frequency of PIK3CA mutations (39%), a lower frequency of PTEN and PIK3R1 mutations (Supplementary Table 6), and genomic losses of PTEN and INPP4B. Other possible druggable mutations included variants within HER family members including two somatic mutations in HER2, two within EGFR, and five within HER3. Pertuzumab, in combination with trastuzumab, targets the HER2–HER3 heterodimer49; however, these data suggest that targeting EGFR with HER2 could also be beneficial. Finally, the HER2E mRNA subtype typically showed high aneuploidy, the highest somatic mutation rate (Table 1), and DNA amplification of other potential therapeutic targets including FGFRs, EGFR, CDK4 and cyclin D1.

[michka]

Wow. This is too complicated on top of my poor English and my chemo brain!

[Laurel]

Hey, Michka! This is too complicated for my martini-bathed brain. Maybe another one would straighten this all out! Lani, I would never suggest you are driving me to drink.....

['lizbeth]

Ki67 Index, HER2 Status, and Prognosis of Patients With Luminal B Breast Cancer


Abstract

Background Gene expression profiling of breast cancer has identified two biologically distinct estrogen receptor (ER)-positive subtypes of breast cancer: luminal A and luminal B. Luminal B tumors have higher proliferation and poorer prognosis than luminal A tumors. In this study, we developed a clinically practical immunohistochemistry assay to distinguish luminal B from luminal A tumors and investigated its ability to separate tumors according to breast cancer recurrence-free and disease-specific survival.

Methods Tumors from a cohort of 357 patients with invasive breast carcinomas were subtyped by gene expression profile. Hormone receptor status, HER2 status, and the Ki67 index (percentage of Ki67-positive cancer nuclei) were determined immunohistochemically. Receiver operating characteristic curves were used to determine the Ki67 cut point to distinguish luminal B from luminal A tumors. The prognostic value of the immunohistochemical assignment for breast cancer recurrence-free and disease-specific survival was investigated with an independent tissue microarray series of 4046 breast cancers by use of Kaplan–Meier curves and multivariable Cox regression.

Results Gene expression profiling classified 101 (28%) of the 357 tumors as luminal A and 69 (19%) as luminal B. The best Ki67 index cut point to distinguish luminal B from luminal A tumors was 13.25%. In an independent cohort of 4046 patients with breast cancer, 2847 had hormone receptor–positive tumors. When HER2 immunohistochemistry and the Ki67 index were used to subtype these 2847 tumors, we classified 1530 (59%, 95% confidence interval [CI] = 57% to 61%) as luminal A, 846 (33%, 95% CI = 31% to 34%) as luminal B, and 222 (9%, 95% CI = 7% to 10%) as luminal–HER2 positive. Luminal B and luminal–HER2-positive breast cancers were statistically significantly associated with poor breast cancer recurrence-free and disease-specific survival in all adjuvant systemic treatment categories. Of particular relevance are women who received tamoxifen as their sole adjuvant systemic therapy, among whom the 10-year breast cancer–specific survival was 79% (95% CI = 76% to 83%) for luminal A, 64% (95% CI = 59% to 70%) for luminal B, and 57% (95% CI = 47% to 69%) for luminal–HER2 subtypes.

Conclusion Expression of ER, progesterone receptor, and HER2 proteins and the Ki67 index appear to distinguish luminal A from luminal B breast cancer subtypes.

['lizbeth]

Molecular Subtypes of Breast Cancer


Although still in the early stages of research, molecular breast cancer subtypes may become useful in planning treatment and developing new therapies. Most studies divide breast cancer into four major molecular subtypes:

• Luminal A
• Luminal B
• Triple negative/basal-like
• HER2 type

These same subtypes also appear in ductal carcinoma in situ [35-36].
Other less common molecular subtypes have also been described including normal breast-like, apocrine molecular type and claudin-low type. Breast cancers that do not fall into any of these subtypes are often listed as unclassified.

At this time, molecular subtypes are used only in research settings and are not a part of standard medical practice. Prognosis and treatment decisions are guided by tumor stage, hormone receptor status and HER2/neu status.

The complex profile of each subtype is determined using molecular and genetic information from tumor cells. However, some characteristics (including hormone receptor status, HER2/neu status and proliferation rate) can be used to roughly define the four major subtypes (see Figure 4.9 below). Much of what is known about the four subtypes is related to these characteristics that are already well understood.


Subtype: Luminal A, These tumors tend to be: ER+ and/or PR+, HER2-, low Ki67, Prevalence: 42-59%

Subtype: Luminal B, These tumors tend to be: ER+ and/or PR+, HER2+ (or HER2- with high Ki67), Prevalence: 6-19%

Subtype: Triple negative/basal-like, These tumors tend to be: ER-, PR-, HER2-, cytokeratin 5/6 + and/or HER1+, Prevalence: 14-20%

Subtype: HER2+, These tumors tend to be: ER-, PR-, HER2+, Prevalence: 7-12%

*These are the most common profiles for each subtype. However, not all tumors within each subtype will have all these features.

[Lani]

unfortunately they have never agreed on how to classify triple positive tumors--some papers place them under Luminal B with other ER+ tumors with hi Ki67s, some place them under luminal-her2 and some put them into the luminal B category which in some papers does not include any her2- tumors. Considering that they make up about 12-15% of breast cancers, this seems an unacceptable situation.

I encourage everyone to TRY to read the entire paper when you can.

[Ellie F]

OK Lani, will try to hang on in there and read the whole paper! Will probably take me the next year as I will have to stop and re read each sentence, then check the science, then HOPE to assimilate it all!
Thank you for taking the time and effort to keep us informed.
Ellie

[Ellie F]

Forgot to add thanks Elizabeth for posting the additional info
Ellie

[bejuce]

Wow, thank you Lani and all of you trying to decipher the research for us! Looks like we still have a lot to learn about these subtypes. It seems to me that breaking down HER-2+ disease among two subtypes is premature as there may be many genetic differences between different HER-2+ tumors. At least that's the message that I'm getting with all this research. Hopefully it will translate into better and effective therapies for all breast cancers.

I still remember my shock when I was diagnosed and learned that the doctors had no way to tell (for the most part) which drugs to assign to each tumor. I thought that surely they would be able to tell from my biopsy which drugs to give. Targeted medicine still has long ways to go...

['lizbeth]

I think what I like best about this news - is that the industry is letting go of the old labels and adopting new ones for cancer subtypes.

It is a paradigm shift in thinking.

[tricia keegan]

Thanks Lani and 'Lizbeth for trying to explain this as I struggled too, I thought as highly triple pos I was luminal B but now I'm not too sure!