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22 mei 2019: Bron: . 2019; 21: 2. Published online 2019 Jan 7

Het is algemeen bekend dat vrouwen met hormonale borstkanker (ER+) hun actieve borstkanker jarenlang onder controle kunnen houden met vormen van hormoontherapie maar dan vele jaren later (tot wel 10 / 20 jaar later) alsnog een recidief krijgen. Femara - letrozole is denk ik een van de meest gebruikte vormen van hormoontherapie.

Recent is een interessante studie gepubliceerd waarin bij een aantal vrouwen met hormonale borstkanker  (N = 42) op verschillende momenten bloedmonsters zijn genomen om daaruit een mutatieprofiel is halen. Daarbij werd gekeken waarom er resistentie en/of een recidief ontstond. En er is daarbij gekeken of het gaat om resistente kankercellen met zelfde DNA profiel als de primaire tumorcellen of om de zogeheten kankerstamcellen, ook wel slapende tumorcellen genoemd die vaak een ander DNA profiel hebben.

Wat opvalt is dat bepaalde specifieke mutaties al te zien in de eerste maanden van de behandeling en kunnen voorspellen of er vele jaren later een recidief op zal treden. Dat wetende zou de eerste behandeling daarop kunnen worden aangepast schrijven de onderzoekers.  

In onderstaande grafiek zie je de momenten van de meding en het onderscheid in resistente tumorcellen en slapende tumorcellen. Gekoppeld aan de kans op een recidief.

 

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Fig. 1

Long-term oestrogen deprivation therapy as a clinical model to investigate breast cancer dormancy and acquired resistance. a Extended (4–45 months) letrozole treatment was exploited as a clinical model of breast cancer dormancy and acquired resistance. Sequential clinical samples from the same patient with no surgery and extended treatment were used to model clinical breast cancer dormancy and resistance. Before (pre, ≤ 0 days), early-on (early, 13–120 days) and long-term (long, > 120 days) neoadjuvant aromatase inhibitor therapy with letrozole. b Dynamic change in tumour size by ultrasound scan (USS) and mean expression of proliferation markers MKI67, PCNA, and MCM2 were used to classify patients into two categories: dormant (blue) and resistant (red). Overall comparisons of classifications per patient based on USS and mean change in proliferation markers with final classification are shown. c The duration of letrozole treatment (days) for samples from dormant (blue) and resistant (red) patients. Each bar represents a sample. Samples are ordered by time on treatment. d Intrinsic subtype classification by PAM50 of samples at each time point. Stacked bar graphs on the right show the percentage of each subtype of samples from dormant and resistant patients. e Kaplan-Meier plot showing disease-free survival probability in patients with dormant versus resistant tumours (log-rank test). Disease-free survival was defined from time of surgery. f Density plot showing the distribution of time to recurrence (in years; defined from time of surgery) in patients with dormant and resistant tumours. CI confidence interval, HR hazard ratio, LumA luminal A, LumB luminal B

Het volledige studierapport: Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours is gratis in te zien en geeft een gedetailleerde beschrijving van de waarde van de metingen van DNA mutaties, waarbij opvalt dat bepaalde specifieke mutaties al te zien in de eerste maanden van de behandeling kunnen voorspellen of er vele jaren later een recidief op zal treden. Dat wetende zou de eerste behandeling daarop kunnen worden aangepast schrijven de onderzoekers.  

Conclusie vertaald: We hebben een eerste studie uitgevoerd van opeenvolgende tumormonsters van borstkankerpatiënten die langdurige neoadjuvante hortmoontherapie met femara / letrozole ontvingen als een klinisch model om slapende tumorcellen en resistente tumorcellen te meten.

Onze analyse suggereert dat moleculaire verschillen tussen slapende en resistente tumoren aanvankelijk subtiel zijn en pas na langdurige behandeling duidelijker worden. Deze studie benadrukt dat veranderingen in DNA-methylatie tijdens de eerste maanden van de behandeling kunnen voorspellen welke patiënte uiteindelijk resistentie / recidief zullen ontwikkelen.

Hier het abstract van de studie met referentielijst:

Epigenetic alterations may lead to escape from dormancy and drive acquired resistance in a subset of patients, supporting a potential role for therapy targeted at these epigenetic alterations in the management of resistance to oestrogen deprivation therapy.

. 2019; 21: 2.
Published online 2019 Jan 7. doi: 10.1186/s13058-018-1089-5
PMCID: PMC6323855
PMID: 30616553

Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours

Abstract

Background

The risk of recurrence for endocrine-treated breast cancer patients persists for many years or even decades following surgery and apparently successful adjuvant therapy. This period of dormancy and acquired resistance is inherently difficult to investigate; previous efforts have been limited to in-vitro or in-vivo approaches. In this study, sequential tumour samples from patients receiving extended neoadjuvant aromatase inhibitor therapy were characterised as a novel clinical model.

Methods

Consecutive tumour samples from 62 patients undergoing extended (4–45 months) neoadjuvant aromatase inhibitor therapy with letrozole were subjected to transcriptomic and proteomic analysis, representing before (≤ 0), early (13–120 days), and long-term (> 120 days) neoadjuvant aromatase inhibitor therapy with letrozole. Patients with at least a 40% initial reduction in tumour size by 4 months of treatment were included. Of these, 42 patients with no subsequent progression were classified as “dormant”, and the remaining 20 patients as “acquired resistant”.

Results

Changes in gene expression in dormant tumours begin early and become more pronounced at later time points. Therapy-induced changes in resistant tumours were common features of treatment, rather than being specific to the resistant phenotype. Comparative analysis of long-term treated dormant and resistant tumours highlighted changes in epigenetics pathways including DNA methylation and histone acetylation. The DNA methylation marks 5-methylcytosine and 5-hydroxymethylcytosine were significantly reduced in resistant tumours compared with dormant tissues after extended letrozole treatment.

Conclusions

This is the first patient-matched gene expression study investigating long-term aromatase inhibitor-induced dormancy and acquired resistance in breast cancer. Dormant tumours continue to change during treatment whereas acquired resistant tumours more closely resemble their diagnostic samples. Global loss of DNA methylation was observed in resistant tumours under extended treatment. Epigenetic alterations may lead to escape from dormancy and drive acquired resistance in a subset of patients, supporting a potential role for therapy targeted at these epigenetic alterations in the management of resistance to oestrogen deprivation therapy.

Electronic supplementary material

The online version of this article (10.1186/s13058-018-1089-5) contains supplementary material, which is available to authorized users.

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