for Jean and others trying to figure out the importance of ER+PR- status

[Lani]

the story just gets more complicated when they look at the groups on the basis of gene expression profile (DNA) or RNA vs. the usual ER and PR testing:

: Breast Cancer Res Treat. 2008 Apr 19 [Epub ahead of print]

Molecular profiles of progesterone receptor loss in human breast tumors.

Creighton CJ, Kent Osborne C, van de Vijver MJ, Foekens JA, Klijn JG, Horlings HM, Nuyten D, Wang Y, Zhang Y, Chamness GC, Hilsenbeck SG, Lee AV, Schiff R.
Dan L. Duncan Cancer Center Division of Biostatistics, Baylor College of Medicine, One Baylor Plaza MS 305, BCM 600, Houston, TX, 77030, USA, creighto@bcm.edu.
Background Patient prognosis and response to endocrine therapy in breast cancer correlate with protein expression of both estrogen receptor (ER) and progesterone receptor (PR), with poorer outcome in patients with ER+/PR- compared to ER+/PR+ tumors. Methods To better understand the underlying biology of ER+/PR- tumors, we examined RNA expression (n > 1000 tumors) and DNA copy number profiles from five previously published studies of human breast cancers with clinically assigned hormone receptor status (ER+/PR+, ER+/PR-, and ER-/PR-). Results We identified an expression "signature" of genes with either elevated or diminished RNA levels specifically in ER+/PR+ compared to ER-/PR- and ER+/PR- tumors. We similarly identified a gene signature specific to ER-/PR- tumors. ER+/PR- tumors, on the other hand, were a mixture of three different subtypes: tumors manifesting the ER+/PR+ signature, tumors manifesting the ER-/PR- signature, and tumors not associating with ER+/PR+ or ER-/PR- tumors (which we considered "true" ER+/PR-). In analyses of both tamoxifen-treated and untreated patients, ER+/PR- breast cancers defined by RNA profiling were associated with poor patient outcome, worse than those with pure ER+/PR+ patterns; these differences were not observed when using clinical assays to assign ER and PR status. ER+/PR- tumors also showed twice as many DNA copy number gains or losses compared to ER+/PR+ and ER-PR- tumors. Targets of transcriptional up-regulation by specific oncogenic pathways, including PI3 K/Akt/mTOR, were enriched in both ER+/PR- and ER-/PR- compared to ER+/PR+ tumors. Conclusion ER+/PR- tumors as defined by RNA profiling represent a distinct subset of breast cancer with aggressive features and poor outcome, despite being clinically ER+. Multigene assays derived from our gene signatures could conceivably provide an improved clinical assay for inferring PR status for prognostic and therapeutic purposes.
PMID: 18425577 [PubMed - as supplied by publisher]

This is from the Kent Osborne, Rachel Schiff group who first published about AIs being more effective in the ER+PR- group and about the triple drug
"cure" of mice with herceptin, pertuzumab (omnitarg) and iressa

food for thought ie, that the results of all those other papers on the topic may need to be reexamined/conclusions revised

[Hopeful]

>>ER+/PR- breast cancers defined by RNA profiling were associated with poor patient outcome, worse than those with pure ER+/PR+ patterns; these differences were not observed when using clinical assays to assign ER and PR status.<<

Lani, I understand this to mean that positivity as determined by the standard pathology tests that are run following biopsy differs from that determined by genomic profiling, is that correct? If so, this makes the proposed offering of ER/PR quantitation by Genomic Testing (the Oncotype Dx company) later this year more provocative, as these assays are the basis for much of the fundamental treatment decisions made in clincal practice.

Thanks for posting.

Hopeful

[Becky]

Saw this paper with Jean at SABCS in December. What it really means is that most ER+/PR+ tumors are just that and most ER-/PR- tumors are just that but many ER+/PR- tumors may actually look molecularly like ER+/PR+ or ER-/PR-. Then, there are those that look different from both and are the true ER+/PR- and they behave differently from the true positives and true negatives.

This is also partially why anti-hormonals work well for some ER+/PR- and not others (because some actually look like ER+/PR+ and others act like ER-/PR-).

In this paper, they also implied that at least with ER+PR- tumors, the Her family was involved but they did not test for Her2 (which they implied was involved much of the time and if it wasn't, then Her1 (aka EGFR) was involved).

It was interesting to say the least.