Newish study below [1].
(Probably only of interest to those already familiar with the PCa estrogen issue.)
When I was examining the PCa literature by hormone in 2004, I was intrigued by the newly discovered estrogen receptor ERβ. There wasn't much to go on, but it seemed that "classic" ER, renamed ERα, generally had no role in prostatic epithelial cells, but in newly diagnosed cases, PCa (epithelial) cells had already suffered a down-regulation of ERβ & an up-regulation of ERα.
Further, that ERα in stromal cells appeared to be growth-promoting, whereas ERβ in epithelial cells resisted the paracrine influence of ERα on growth.
In contrast, at diagnosis, most men had "wild type" androgen receptor [AR]. The mutations common to AR in PCa were induced by treatment.
So it's been a puzzle to me that Dr. Myers has denied any role for estrogen in PCa, & Dr. Morgentaler seems to have made no mention of estrogen.
Anyway, my initial concern was to keep androgen & estrogen in balance. I also used phytoestrogens that have a strong binding affinity for ERβ, but not for ERα.
It never occurred to me that ADT might induce mutations in ER. The finding of the new study suggests that estrogen continues to have a role in advanced PCa.
"A select number of mutations for the ESR1 gene, coding for ERα, have been explored for breast cancer. As ERs are also expressed by non‐cancerous cells, ER mutations have been reported as detected proportions relative to wild‐type ER, as a mutation frequency. The presence of certain ESR1 mutations has been associated with acquired resistance to aromatase inhibitor therapy in patients with advanced breast cancer."
"Using the genomic datasets available publicly, the prevalence of ESR1 and ESR2 mutations or copy number change was 4% (5/150) in patients with metastatic or advanced prostate cancer, compared to 2% (11/492) in patients with early prostate cancer. Interestingly, there was significantly higher prevalence of ER aberrations among patients with neuroendocrine prostate cancer compared to early prostate cancer (17% vs 2% ...). The predominant aberration was increased copy number. Altered ER copy number or mutation was associated with poorer overall survival among the patients with early prostate cancer.., although there was no significant difference in progression‐free survival. From our preliminary analysis, there was convincing evidence to further investigate the role of ERs as markers in advanced prostate cancer."
"Discussion
"In the present study we explored the detection of circulating ER mutants and splice variants in men with advanced prostate cancer. Four of the six ESR1 mutations tested (E380Q, L536Q, Y537S and D538G) were detected in patient blood‐derived RNA samples. Factors influencing the detection of these ESR1 mutations include volume of disease, as well as the use of different therapies that target hormone signalling. In addition, the metabolic microenvironment of the disease may also impact on the detection of these signalling markers, through their association with disease progression and aggressiveness.
"Initial preliminary genomic data obtained from prostate cancer databases revealed ER aberrations in up to 17% of advanced prostate cancer tumour tissues with neuroendocrine features, compared to early prostate tumours (2%; Fig. 1). The increase in ER aberrations in advanced prostate cancers may be explained by the selection pressure from therapies, especially those targeting hormone signalling pathways.
"The frequency of detection of ESR1 mutations in this study (67%) is comparable to previous studies investigating the same ESR1 mutations in metastatic breast cancer. Breast cancer studies using ddPCR to detect circulating tumour DNA have reported mutation‐positive frequencies varying from 14.0% to 82.0%. The prevalence of the D538G mutation has been reported to be up to 83.3% in metastatic breast cancer samples. In comparison, we detected D538G in 24.5% of our prostate cancer samples. To contrast with other hormone receptors investigated in men with advanced prostate cancer, reported AR mutations range from 8.2% to 45%, where they have been associated with poor outcomes. In the present study we used RNA samples derived from blood as an indirect measure of cfRNA and, in turn, circulating tumour RNA, to identify somatic mutations associated with prostate cancer and to analyse RNA splice variants. Previously ESR1 mutation analysis has been performed directly using cfDNA. The presence of these low‐frequency mutations in the absence of germline mutations suggests that they may be derived from cancer. In contrast, the splice variants are likely to be derived from non‐malignant and malignant cells, especially as all six ER splice variants were detectable in almost all patients and normal healthy controls. Our blood‐derived RNA findings may not be comparable, however, with previous studies that reported ER splice variants in tissue and used other assays such as immunohistochemistry.
"The development of these ER ddPCR assays assists our early investigation of ER biology in advanced prostate cancer. The use of the ER variant ddPCR assays may be applied to CTC samples for analysing tumour‐specific genes or the effects of therapies affecting ER signalling. Data from the present study indicate that changes in ER splice variants may be involved in CRPC biology, while the explored ESR1 mutations had limited potential utility. ERβ splice variants may also be explored further for association with progression for patients on chemotherapy or androgen signalling targeted therapy.
"In addition, the efficient analysis of variants as biomarkers in advanced prostate cancer can be further aided and coordinated on a global scale. The systematic collection of data through the development and analysis of registries that use refined quality indicators can ensure consistency of information that can provide a framework for biomarker work in advanced prostate cancer.
"In summary, the present exploratory study has provided evidence that ER mutants and splice variants are present in men with advanced prostate cancer, warranting their investigation in larger prospective studies."
-Patrick
[1] onlinelibrary.wiley.com/doi...
BJU InternationalVolume 124, Issue S1
Original Article Free Access
Circulating oestrogen receptor mutations and splice variants in advanced prostate cancer
Liang G. Qu Hady Wardan Ian D. Davis Mahesh Iddawela Pavel Sluka Carmel J. Pezaro
First published: 15 May 2019
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Abstract
Objective
To characterize circulating oestrogen receptor ( ER) mutants and splice variants in men with advanced prostate cancer.
Materials and Methods
Sequential blood samples were obtained from men with advanced prostate cancer, and from healthy controls. Blood‐derived RNA samples were analysed using droplet digital PCR for the presence of six ERα mutations (E380Q, L536Q, Y537C, Y537S, Y537N and D538G), and six ERα and ERβ splice variants (ERα‐66, ERα‐36, ERβ1, ERβ2, ERβ4 & ERβ5).
Results
A total of 94 samples were collected from 42 men with advanced prostate cancer. Four mutations (E380Q, L536Q, Y537S and D538G) and all six splice variants were detected in patient samples. Splice variants were detectable in non‐cancer control samples. The presence of ER mutations was associated with bone metastases and castration resistance. ERβ splice variant concentrations decreased after successive lines of treatment.
Conclusions
The ER mutations were detectable in plasma from patients with advanced prostate cancer. ER splice variants were frequently detected in both men with and without prostate cancer.
Advanced Prostate Cancer
Advanced Metastatic Prostate Cancer
Cycling with Advanced Prostate Cancer
Aggressive Variant Prostate Cancer (AVPC)
