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Elk bedrag is welkom. En we zijn een ANBI instelling dus uw donatie of gift is in principe aftrekbaar voor de belasting.

En als donateur kunt u ook korting krijgen bij verschillende bedrijven, waaronder bij Medpro voor o.a. prostasol  een veelgebruikt natuurlijk middel bij prostaatkanker als alternatief voor hormoontherapie

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1 november 2016: Bron: The Lancet en ESMO 2016

Net zoals bij borstkanker (bv. de Mammaprint) zijn Amerikaanse onderzoekers erin geslaagd om ook voor prostaatkanker een genenmutatietest (PROPOS) te ontwikkelen die voorspellend is voor de kansen op overall overleving.

Zo presenteerde Daniel Spratt, MD, Chief of the Genitourinary Radiotherapy Program at the University of Michigan and Director of the University of Michigan Spine Oncology Program, Ann Arbor de uitkomsten van een naar zijn zeggen grootste datastudie ooit uitgevoerd bij prostaatkankerpatiënten de resultaten van hun studie op de 58th Annual Meeting of the American Society for Radiation Oncology (ASTRO),1

PROPOS test

Bron foto: Decipher® Biopsy test now available

Kernpunten uit deze studie:

Prostate Cancer Subtypes

  • The largest study of genomics to date in prostate cancer has identified and validated three intrinsic subtypes: A, B, and C.
  • These subtypes have been retrospectively and prospectively validated in large numbers of tissue samples from newly diagnosed patients treated with radical prostatectomy.
  • Subtype A has the best prognosis, whereas subtypes B and C have a twofold greater response to radiation than subtype A, suggesting that subtype A patients may not need radiotherapy.
  • With further study and stratification of study patients by genomic subtype, these data could identify which patients need specific treatment.

De onderzoekers hebben dus drie verschillende clusters van uitgesproken aan prostaatkanker gerelateerde moleculaire subtypes geïndentificeerd en onderzocht: subtypes A, B, en C.

De genendata van 4,236 tumorweefsel van mannen met nieuw gediagnosteerde lokale prostaatkanker behandeld met een radicale verwijdering van de prostaat zijn ingevoerd in een onderzokeksmodel dat de 100 meest voorkomende genen identificeerde.  Gebaseerd op de genenexpressie (verhoogd versus verlaagd) werden drie clusters van genen subtypes geïdentificeerd en onderverdeeld in subtypes A, B, en C.

Deze drie subtypes hadden een verschillende uitkomst van de uitzaaiingen op afstand vrije overall overleving op 10 jaar: subtype A, 73.6%; subtype B, 64.4%; en subtype C, 57.1%. Subtype A bleek de beste kansen op overall overleving zonder uitzaaiingen op afstand te geven. Een verschil van 16,5% met subtype C wat een groot verschil is op 10 jaar bij deze vorm van kanker. Omdat ook voor prostaatkanker heel veel behandelopties mogelijk zijn.

De specifiek gebruikte moleculaire genenmutaties worden niet genoemd in de studie maar is te begrijpen omdat het bedrijf dat deze test heeft ontwikkeld die nog even geheim wilt houden denk ik. Zij stellen wel dat de test beschikbaar is voor artsen en wetenschappers om deze aan te vragen.

In een aparte deelstudie, gepubliceerd in The Lancet blijkt dat subtype A de beste resultaten geeft op de kansen om de10 jaar te overleven zonder uitzaaiingen van de ziekte met of zonder radiotherapie vooraf aan een operatie (Da Vinci). Subtype A patiënten, die de beste prognose bleken te hebben, reageerden echter minder goed op radiotherapie - bestraling vooraf aan een operatie in vergelijking met subtypes B en C. Dit betekent volgens de onderzoekers dat patiënten met een genenprofiel van subtype B en C het beste vooraf aan een operatie radiotherapie - bestraling kan worden aangeboden. 

Het volledige studierapport van Development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched, retrospective analysis is tegen betaling in te zien.

Het volledige studierapport: Identification and Validation of Intrinsic Subtypes of Prostate Cancer is gepubliceerd in Radiation Oncology

Hier de twee abstracten:

Prognostic and Predictive Molecular Subtypes of Prostate Cancer Identified

Identification and Validation of Intrinsic Subtypes of Prostate Cancer

D.E. Spratt
,
S.G. Zhao
,
S.L. Chang
,
M.R. Cooperberg
,
N.G. Erho
,
C. Speers
,
R. Mera
,
Y.S. Niknafs
,
P.L. Nguyen
,
R.B. Den
,
A.P. Dicker
,
E.A. Klein
,
R.J. Karnes
,
E.M. Schaeffer
,
E. Davicioni
,
P. Carroll
,
A. Chinnaiyan
,
S.A. Tomlins
,
A.E. Ross
,
F.Y. Feng

6

Purpose/Objective(s)

To identify the first ever intrinsic molecular subtypes of primary prostate cancer through unbiased high-throughput analyses.

Materials/Methods

RNA expression patterns captured from high-density microarrays and transcriptome sequencing were analyzed in 4,236 primary prostate cancer samples from nine independent cohorts. K-medoids clustering was used in training and validation sets to identify intrinsic subtypes. The subtypes were correlated with distant metastasis-free survival (DMFS). The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used to identify biological functions enriched in the subtype genes. Mutation analysis was performed using the cBioPortal for Cancer Genomics.

Results

Clustering in the training dataset initially was strongly influenced by stromal genes, likely indicative of tumor content, as well as genes strongly associated with warm ischemia, likely indicative of elapsed time between specimen harvest and fixation. After these tumor extrinsic factors were removed, we identified three distinct groups based on 100 genes (PC100). These findings were validated in the remaining seven frozen or FFPE retrospective cohorts as well as in a prospective validation cohort of 2,113 patients. The intrinsic subtypes were associated with known drivers of prostate cancer, including AR and ERG, but do not appear to be driven by mutations or rearrangements. The 10-year rates of DMFS across the three subtypes were 73.6% (A), 64.4% (B), and 57.1% (C) (B vs. A: Cox HR = 1.31 [95%CI 1.04-1.66], P = 0.02, C vs. A: HR = 1.65 [1.29-2.10], P = 0.0001). The subtypes were independently associated with DMFS after adjusting for clinicopathologic variables (B vs. A: Cox HR = 1.31 [1.03-1.65], P = 0.026, C vs. A: HR = 1.33 [1.04-1.71], P = 0.024). Furthermore, on multivariate interaction analysis, subtype C was significantly associated with response to post-operative radiotherapy (Wald P = 0.0016). Within the 100 genes, enriched biological functions relate to clusters of genes governing protein degradation, RNA processing, apoptosis, the cell cycle, ATP synthesis, and a large cluster of genes relating to protein localization.

Conclusion

We have identified three novel intrinsic subtypes of prostate cancer in the largest study of its kind, and validated our findings across sequencing platforms, storage methods, and within both retrospective and prospective cohorts. In defining unique biological clusters of disease, the PC100 represents a step towards personalization of prostate cancer care. Future work will focus on validating the predictive capacity of these subtypes to therapy such as radiation therapy.

Author Disclosure: D.E. Spratt: Research Grant; Prostate Cancer Foundation. S.G. Zhao: Travel Expenses; GenomeDx. S. Chang: None. M.R. Cooperberg: Research Grant; GenomeDx. Honoraria; Takeda. Consultant; Myriad/Astellas, Dendreon, Janssen. N.G. Erho: None. C. Speers: Patent/License Fees/Copyright; Patent. R. Mera: None. Y.S. Niknafs: Patent/License Fees/Copyright; Patent. P.L. Nguyen: Consultant; Medivation, GenomeDx, Ferring, Nanobiotix. R.B. Den: None. A.P. Dicker: Honoraria; Merck, Pfizer, EMD Serono. E.A. Klein: Research Grant; GenomeDx. Speaker's Bureau; Genomic Health. R.J. Karnes: None. E.M. Schaeffer: Consultant; GenomeDx/Myriad Genetics. E. Davicioni: Patent/License Fees/Copyright; GenomeDx. P. Carroll: Honoraria; Takeda/Genomic Health. Consultant; Janssen and Medivation. A. Chinnaiyan: Advisory Board; Wafergen and Thermofisher. Patent/License Fees/Copyright; Patent. S.A. Tomlins: Research Grant; Thermo Fisher. Honoraria; Ventana Medical Systems. Consultant; Ventana Medical Systems. Patent/License Fees/Copyright; Patent. A.E. Ross: Consultant; GenomeDx. F.Y. Feng: Consultant; Medivation/Astellas, GenomeDx, Celgene, Varian Medical Systems. Partnership; PFS Genomics. Patent/License Fees/Copyright; Patent.

Prognostic and Predictive Molecular Subtypes of Prostate Cancer Identified

Development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched, retrospective analysis

Shuang G Zhao, MD
,
S Laura Chang, PhD
,
Daniel E Spratt, MD
,
Nicholas Erho, MSc
,
Prof Menggang Yu, PhD
,
Hussam Al-Deen Ashab, MSc
,
Mohammed Alshalalfa, PhD
,
Corey Speers, MD
,
Scott A Tomlins, MD
,
Elai Davicioni, PhD
,
Prof Adam P Dicker, MD
,
Prof Peter R Carroll, MD
,
Matthew R Cooperberg, MD
,
Prof Stephen J Freedland, MD
,
R Jeffrey Karnes, MD
,
Ashley E Ross, MD
,
Prof Edward M Schaeffer, MD
,
Robert B Den, MD
,
Paul L Nguyen, MD
,
Dr Felix Y Feng, MD,correspondencePress enter key for correspondence information
Contributed equally as first authors
Contributed equally as last authors

DOI: http://dx.doi.org/10.1016/S1470-2045(16)30491-0

Summary

Background

Postoperative radiotherapy has an important role in the treatment of prostate cancer, but personalised patient selection could improve outcomes and spare unnecessary toxicity. We aimed to develop and validate a gene expression signature to predict which patients would benefit most from postoperative radiotherapy.

Methods

Patients were eligible for this matched, retrospective study if they were included in one of five published US studies (cohort, case-cohort, and case-control studies) of patients with prostate adenocarcinoma who had radical prostatectomy (with or without postoperative radiotherapy) and had gene expression analysis of the tumour, with long-term follow-up and complete clinicopathological data. Additional treatment after surgery was at the treating physician’s discretion. In each cohort, patients who had postoperative radiotherapy were matched with patients who had not had radiotherapy using Gleason score, prostate-specific antigen concentration, surgical margin status, extracapsular extension, seminal vesicle invasion, lymph node invasion, and androgen deprivation therapy. We constructed a matched training cohort using patients from one study in which we developed a 24-gene Post-Operative Radiation Therapy Outcomes Score (PORTOS). We generated a pooled matched validation cohort using patients from the remaining four studies. The primary endpoint was the development of distant metastasis.

Findings

In the training cohort (n=196), among patients with a high PORTOS (n=39), those who had radiotherapy had a lower incidence of distant metastasis than did patients who did not have radiotherapy, with a 10-year metastasis rate of 5% (95% CI 0–14) in patients who had radiotherapy (n=20) and 63% (34–80) in patients who did not have radiotherapy (n=19; hazard ratio 0·12 [95% CI 0·03–0·41], p<0·0001), whereas among patients with a low PORTOS (n=157), those who had postoperative radiotherapy (n=78) had a greater incidence of distant metastasis at 10 years than did their untreated counterparts (n=79; 57% [44–67] vs 31% [20–41]; HR 2·5 [1·6–4·1], p<0·0001), with a significant treatment interaction (pinteraction<0·0001). The finding that PORTOS could predict outcome due to radiotherapy treatment was confirmed in the validation cohort (n=330), which showed that patients who had radiotherapy had a lower incidence of distant metastasis compared with those who did not have radiotherapy, but only in the high PORTOS group (high PORTOS [n=82]: 4% [95% CI 0–10] in the radiotherapy group [n=57] vs 35% [95% CI 7–54] in the no radiotherapy group [n=25] had metastasis at 10 years; HR 0·15 [95% CI 0·04–0·60], p=0·0020; low PORTOS [n=248]: 32% [95% CI 19–43] in the radiotherapy group [n=108] vs 32% [95% CI 22–40] in the no radiotherapy group [n=140]; HR 0·92 [95% CI 0·56–1·51], p=0·76), with a significant interaction (pinteraction=0·016). The conventional prognostic tools Decipher, CAPRA-S, and microarray version of the cell cycle progression signature did not predict response to radiotherapy (pinteraction>0·05 for all).

Interpretation

Patients with a high PORTOS who had postoperative radiotherapy were less likely to have metastasis at 10 years than those who did not have radiotherapy, suggesting that treatment with postoperative radiotherapy should be considered in this subgroup. PORTOS should be investigated further in additional independent cohorts.


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