11 december 2015: lees ook dit artikel: 

https://kanker-actueel.nl/NL/chemo-voor-borstkanker-met-type-luminal-a-hormoongevoelig-met-er-en-pr-pos-en-her2-neg-is-zinloos-en-geeft-geen-enkel-verschil-in-10-jaars-overleving-in-vergelijking-met-geen-chemo-biij-vrouwen-in-leeftijd-voor-de-overgang.html

12 mei 2009: Bronnen:
 
Het NCI -  National Cancer Institute heeft een negatief rapport uitgebracht over de chemo  Adriamycin (doxorubin) en andere zogeheten anthracycline chemo's (epirubicine en idarubicin) bij borstkanker. Eerder hadden studies bewezen dat slechts een beperkt aantal borstkankerpatienten (met HER2-Neu status positief) profiteert van chemo  (ca. 20%) De rest ca. 80% zou niet gebaat zijn met anthracycline chemo's.  Deze gegevens zijn nu ondersteund door een nieuwe Canadese studie, gepubliceerd  in het Journal of the National Cancer Institute (O'Malley 2009), met een begeleidend redactioneel schrijven door dr. Slamon. Zie hieronder het abstract van de studies van dr. O'Mailey en opmerkingen van dr. Slamon.
Kern is dat de onderzoekers  hebben gezocht bij hun deelnemende borstkankerpatienten naar de aanwezigheid of afwezigheid van bepaalde markers op de kankercellen, genaamd TOP2A en HER2. Hun belangrijkste bevinding was dat patiënten bij wie de tumoren veranderingen aantoonden in deze markers zij inderdaad langer overleven met een CEF - chemokuur (het anthracycline-bevattende regime bevat, naast cyclofosfamide en 5-FU, ook epirubicine, een anthracycline ) dan degenen die behandeld werden met CMF (naast cyclofosfamide en 5-FU, bevat deze chemokuur het niet-anthracycline methotrexaat). Maar zij toonden ook aan dat patiënten die geen TOP2A markerwijzigingen hadden geen significante verbetering van de overleving hadden (O'Malley 2009). 
 
Slamon commentaar in zijn begeleidende redactioneel:
"Dit verslag is de laatste in een reeks publicaties die vraagtekens zet bij de algemene veronderstelling dat er sprake is van een gelijk positief effect voor alle borstkanker patiënten die op anthracycline gebaseerde adjuvante therapie ontvangen, in tegenstelling tot niet-anthracycline-bevattende adjuvante therapie" (Slamon 2009). 

Wat betekent dit nu? Algemeen staat Adriamycin in de wereld van toxische chemotherapie, Adriamycin (en andere anthracyclines) berucht voor hun bijwerkingen. Deze bijwerkingen omvatten cardiale toxiciteit waaronder congestief hartfalen evenals beenmerg dysfunctie, met inbegrip van acute leukemie en myelodysplasia. Deze ernstige bijwerkingen zijn reeds lang bekend. Echter, Slamon nu presenteert gegevens uit een langere follow-up waaruit blijkt dat  oncologen die aan borstkanker patiënten adjuvante anthracyclines voor hun borstkanker toedienden eerdere evaluaties kunnen hebben onderschat op lange-termijn toxiciteiten" (Slamon 2009). Met andere woorden, het nieuws over de lange-termijn effecten van anthracyclines is erger dan werd gedacht. Salmon pleit dan ook voor vooraf goede betrouwbare testen zoals ook chemogevoeligheidstesten. (Mammaprint bv.) en uiteraard vaststellling van Her2-Neu status 

Slamon: "We weten nu dat de moleculaire diversiteit van menselijke borstkanker veel complexer is en dat de klinische voordelen van verschillende systemische therapeutische interventies kunnen worden beïnvloed door het moleculaire subtype van de ziekte" (ibid.).
Een andere recent gepubliceerde studie toont aan dat borstkankerpatienten die driedubbel negatieve markers laten zien op oestrogeen, progesteron en HER2-Neu receptoren (dan is er sprake van een zeer agressieve vorm van borstkanker)  ook zij gebaat zijn bij een geode genentest want sommigen zouden ook baat kunnen heben bij bepaalde vormen van chemo enz. Zie studieabstract onderaan.

Topoisomerase II Alpha and Responsiveness of Breast Cancer to Adjuvant Chemotherapy

F. P. O’Malley, S. Chia, D. Tu, L. E. Shepherd, M. N. Levine, V. H. Bramwell, I. L. Andrulis, K. I. Pritchard

Affiliations of authors: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada (FPO, ILA); Department of Laboratory Medicine and Pathobiology (FPO, ILA), Sunnybrook Odette Cancer Centre (KIP), and Department of Medicine (KIP), University of Toronto, Toronto, Ontario, Canada; Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada (SC); Department of Medical Oncology, University of British Columbia, Vancouver, British Columbia, Canada (SC); Department of Medical Oncology, National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario, Canada (DT, LES); Department of Medical Oncology, McMaster University, Hamilton, Ontario, Canada (MNL); Department of Medical Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada (VHB); Department of Medical Oncology, University of Calgary, Calgary, Alberta, Canada (VHB); Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (ILA)

Correspondence to: Kathleen I. Pritchard, MD, Sunnybrook Odette Cancer Centre, University of Toronto, 2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5 (e-mail: kathy.pritchard@sunnybrook.ca ).

Background: Amplification or deletion of the topoisomerase II alpha (TOP2A) gene in breast cancers has been postulated to be more closely associated with responsiveness to anthracycline-containing chemotherapy than amplification of the human epidermal growth factor receptor type 2 (HER2) gene.

Methods: We studied 438 tumors from 710 premenopausal women with node-positive breast cancer who received cyclophosphamide, epirubicin, and 5-fluorouracil (CEF) or cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant chemotherapy in the randomized National Cancer Institute of Canada Clinical Trials Group Mammary 5 (MA.5) trial. TOP2A alterations and HER2 amplification were quantified by fluorescence in situ hybridization. The association of TOP2A and HER2 status with recurrence-free survival (RFS) and overall survival (OS) in the two treatment groups was analyzed using Kaplan–Meier curves, the log-rank test, and Cox proportional hazard models. All statistical tests were two-sided.

Results: In patients whose tumors showed TOP2A alterations (either amplifications or deletions), treatment with CEF was statistically significantly superior to treatment with CMF in terms of RFS (adjusted hazard ratio = 0.35, 95% confidence interval = 0.17 to 0.73, P = .005) and OS (adjusted HR = 0.33, 95% CI = 0.15 to 0.75, P = .008). In patients without TOP2A amplification or deletion, the corresponding adjusted hazard ratios for RFS and OS were 0.90 (95% CI = 0.66 to 1.23, P = .49) and 1.09 (95% CI = 0.77 to 1.56, P = .62). Adjusted tests of interaction between treatment and TOP2A status were P = .09 for RFS and P = .02 for OS. Adjusted tests of interaction between treatment and HER2 status were P = .008 for RFS and P = .02 for OS.

Conclusion: TOP2A gene alterations (amplifications or deletions) are associated with an increase in responsiveness to anthracycline-containing chemotherapy regimens relative to non-anthracycline regimens that is similar to that seen in patients with HER2 amplification.

12 mei 2009: Bron: 1: J Natl Cancer Inst. 2009 May 6;101(9):644-50. Epub 2009 Apr 28.Click here to read Links

 

 

 
Comment in:
J Natl Cancer Inst. 2009 May 6;101(9):615-8.

Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy.

Sunnybrook Odette Cancer Centre, University of Toronto, 2075 Bayview Ave, Toronto, Ontario, Canada.

BACKGROUND: Amplification or deletion of the topoisomerase II alpha (TOP2A) gene in breast cancers has been postulated to be more closely associated with responsiveness to anthracycline-containing chemotherapy than amplification of the human epidermal growth factor receptor type 2 (HER2) gene.

METHODS: We studied 438 tumors from 710 premenopausal women with node-positive breast cancer who received cyclophosphamide, epirubicin, and 5-fluorouracil (CEF) or cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant chemotherapy in the randomized National Cancer Institute of Canada Clinical Trials Group Mammary 5 (MA.5) trial. TOP2A alterations and HER2 amplification were quantified by fluorescence in situ hybridization. The association of TOP2A and HER2 status with recurrence-free survival (RFS) and overall survival (OS) in the two treatment groups was analyzed using Kaplan-Meier curves, the log-rank test, and Cox proportional hazard models. All statistical tests were two-sided.

RESULTS: In patients whose tumors showed TOP2A alterations (either amplifications or deletions), treatment with CEF was statistically significantly superior to treatment with CMF in terms of RFS (adjusted hazard ratio = 0.35, 95% confidence interval = 0.17 to 0.73, P = .005) and OS (adjusted HR = 0.33, 95% CI = 0.15 to 0.75, P = .008). In patients without TOP2A amplification or deletion, the corresponding adjusted hazard ratios for RFS and OS were 0.90 (95% CI = 0.66 to 1.23, P = .49) and 1.09 (95% CI = 0.77 to 1.56, P = .62). Adjusted tests of interaction between treatment and TOP2A status were P = .09 for RFS and P = .02 for OS. Adjusted tests of interaction between treatment and HER2 status were P = .008 for RFS and P = .02 for OS.

CONCLUSION: TOP2A gene alterations (amplifications or deletions) are associated with an increase in responsiveness to anthracycline-containing chemotherapy regimens relative to non-anthracycline regimens that is similar to that seen in patients with HER2 amplification.

PMID: 19401546 [PubMed - in process]

Bron: 1: Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2009 Mar;153(1):13-7.Click here to read Links

 

Triple negative breast cancer--current status and prospective targeted treatment based on HER1 (EGFR), TOP2A and C-MYC gene assessment.

Department of Paediatrics, Faculty of Medicine and Dentistry, Laboratory of Experimental Medicine, Palacky University and University Hospital, Olomouc, Czech Republic. hajduchm@gmail.com

BACKGROUND: Every year about one million women worldwide are diagnosed with breast cancer which is the most common malignancy in female. Of these, triple negative breast carcinoma represents 10-17 %. Triple negative breast carcinomas, characterized by estrogen, progesterone and HER2 receptor negativity are very aggressive tumours with poor prognosis. Individualized treatment (tailored therapy) based on molecular biology markers of tumor and patient is the trend in clinical practice these days. However, molecular targets and predictors for the treatment of triple negative breast carcinoma do not currently exist.

METHODS AND RESULTS: This minireview focuses on biomarkers (HER1/EGFR, TOP2A and C-MYC genes) that may predict the response of triple negative breast carcinoma patients to chemotherapy and/or targeted biological treatment with a summary of current knowledge about them.

CONCLUSION: HER1 belonging to the HER family of receptors plays an important role in cell proliferation, migration and protection against apoptosis. HER1 protein could be targeted by monoclonal antibodies and/or tyrosine kinase inhibitors (TKIs). Given signal pathway complexity and HER family member cooperation, it may be better to simultaneously target a number of these receptors (e.g. HER1/HER2 by lapatinib). Thus, HER1 assessment could reveal a particular breast cancer patient group with probably good response to HER1 targeted therapy. TOP2A gene, encoding topoisomerase II alpha (target for anthracyclines) is predictive of response to anthracycline therapy. TOP2A aberrations (amplification, deletion) are found in up to approximately 30-90 % of HER2 amplified breast cancer and amplifications are more common than deletions. Recent publications describe TOP2A amplification also in 2.7-8.8 % HER2 nonamplified breast cancers. Patients with a pathologic complete response to anthracycline based neoadjuvant chemotherapy had a good overall prognosis regardless of molecular subtype of breast cancer. These results suggest that particularly tumors with a complete pathological response to anthracyclines could have TOP2A amplification. C-MYC encodes nuclear DNA binding proteins that regulate proliferation and apoptosis; amplification is associated with poor prognosis and hormonally negative breast carcinoma.

PMID: 19365520 [PubMed - indexed for MEDLINE]

 

 

 


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