11 augustus 2014: wie een engelstalig artikel The PI3K/AKT/mTOR Pathway in Breast Cancer wilt over de behandelingsopties voor borstkanker met afwijkingen in genoemde pathways stuurt ons een e-mail: redactie@kanker-actueel.nl  en we kunnen u dat digitaal toesturen.

Via onze contacten kunnen wij onze donateurs aanbieden om samen met U een aanvraag te doen voor een biomoleculair receptoren- en genenonderzoek bij een bedrijf dat wereldleider is op dit gebied om te laten bepalen welke medicijnen en behandelingen voor uw vorm en stadium van kanker de meeste kans op succes bieden. Zie onder regulier - personalised medicine  of klik hier. 

Indien u interesse hebt mail aan: redactie@kanker-actueel.nl t.a.v. Kees onze webmaster

30 april 2014: Bron: San Antonio Breast Cancer Symposium december 2013

Borstkankerpatiënten met een Her2 Neu positieve status en een positieve AR status (hormoongevoelig) en een overexpressie van het PKI3CA enzym hebben een veel kleinere kans om te profiteren vooraf aan eventuele operatie van een behandeling met chemo plus herceptin dan borstkankerpatiënten zonder overexpressie van het PKI3CA eiwit. Het verschil bleek 6,5% vs 30,8 respectievelijk in het bereiken van een partiële remissie voor patiënten met wel of geen overexpressie van het PKI3CA eiwit.

Dit blijkt uit een geradomiseerde studie postpectief uitgevoerd op het weefsel van totaal 737 patiënten met borstkanker verdeeld over twee gerandomiseerde studies. De GeparSixto (G6)en GeparQuinto (G5) studies.

Het volledige studierapport van de G6 studie: Neoadjuvant treatments for triple-negative breast cancer (TNBC): waaruit deelnemers op gerandomiseerde basis zijn geselecteerd voor de biomarkerstudie is in 2012 gepubliceerd en gratis in te zien. Het abstract daarvan staat onderaan dit artikel.

Het volledige studierapport van de G5 studie: Neoadjuvant bevacizumab and anthracycline–taxane-based chemotherapy in 678 triple-negative primary breast cancers; results from the geparquinto study (GBG 44)†
waaruit ook deelnemers zijn geselecteerd voor de biomarkerstudie is in 2012 gepubliceerd. Het abstract daarvan staat ook onderaan dit artikel.

Neoadjuvant treatments for triple-negative breast cancer (TNBC)

Table 1.

Pathological complete response rates with current neoadjuvant treatments and regimens in triple-negative breast cancer

ChemotherapyTNBC (N)pCR (%)pCR definitionReference
Anthracycline/taxane
 FEC/FAC/AC 14 20% (P = 0.0001) pCR in breast and axilla Liedtke et al. [13]
 TFEC/TFAC 35 28% (P = 0.0071)
 Anthracyclines/taxanesa 542 34% TNBC (P < 0.001) pCR in breast and axilla von Minckwitz et al. [6]
24% non-TNBC (P < 0.001)
Platinum alone
 Cisplatinb 28 21% pCR in breast Silver et al. [25]
Platinum/taxane
 Paclitaxel/carboplatinc 12 67% versus 12% (ER+/HR−) (P = 0.002) pCR in breast and axilla Sikov et al. [9]
 Paclitaxel/carboplatind 24 33% pCR in breast plus axilla Chen et al. [45]
 Docetaxel/carboplatine 13 77% pCR in breast Kern et al. [46]
 Docetaxel/carboplatinf 9 44% pCR in breast and axilla Roy et al. [47]
 Docetaxel/carboplating 11 55% pCR in breast Chang et al. [48]

  • TNBC, triple-negative breast cancer; pCR, pathological complete response; FEC, fluorouracil, epirubicin, cyclophosphamide; FAC, fluorouracil, doxorubicin, cyclophosphamide; AC, doxorubicin, cyclophosphamide; TFEC, weekly/once every 3 weeks paclitaxel/docetaxel followed by fluorouracil, epirubicin, cyclophosphamide; TFAC, weekly/once every 3 weeks paclitaxel/docetaxel followed by fluorouracil, doxorubicin, cyclophosphamide; ER, oestrogen receptor; HR, hormone receptor; AUC, area under curve.

  • aMultivariable analysis of treatment characteristics.

  • bFour treatments of cisplatin at 75 mg/m2 every 21 days were administered, 95% CI 9% to 43%.

  • cCarboplatin AUC 6 q4w and paclitaxel 80 mg/m2 weekly for 16 weeks.

  • dSingle-arm study: weekly paclitaxel 80 mg/m2 plus carboplatin AUC 2 weekly.

  • eDocetaxel 75 mg/m2 plus carboplatin AUC 6 q3w × 6 cycles, ongoing single-arm study.

  • fDocetaxel 75 mg/m2 plus carboplatin AUC 3 q2w + G-CSF × 4 cycles, single-arm study.

  • gDocetaxel 75 mg/m2 plus carboplatin AUC 6 q3w × 4 cycles, single-arm study.

Hier het zo goed als letterlijk vertaalde abstract van de biomarkerstudie:
 
Studieresultaten: PIK3CA Gene Mutations Make HER2 - and Hormone Receptor - positive  Breast Cancers Treatment resistant

Resultaten:
In de G6 study, 595 patiënten met HER2+ve of TN primaire borstkanker (BC) zijn gerandomiserd ingedeeld in de periode september 2011 tot november 2012. Gemiddelde leeftijd was 47 jaar (range 21 - 78 jaar); de meeste tumoren waren cT2 (65%); cN0 (57%); ductal invasief (93%), graad 3 (65%); Binnen de HER2+ve groep was 62% HR - positief. Op moment van evaluatie waren totaal 512 patiënten met het PIK3CA genotypebeschikbaar voor evaluatie. 240 patiënten met HER2+ve en 272 met TN ziekte.

Overall werd bij 13.1% tenminste een mutatie gevonden, bij HER2+ve: 19.2% en TNBC bij 7.7%. PIK3CA mutaties werden numeriek vaker gevonden in de HER2+ve/HR+ve in vergelijking met de HER2+ ve/HR- ve groep: 21.5% vs 15.4% respectievelijk (p=0.245).

Overall, een partiële complete remissie (pCR) was stastisch significant bij patienten met een PIK3CA mutatie vergeleken tot de wild type groop, dus met geen PIK3CA mutatie (22.7% vs. 43.6%; p=0.001). Dit effect was alleen statistisch significant in de HER2+ve groep (17.8% vs. 36.8%; p=0.015) vergeleken met de groep met TNBC (33.3% vs. 49%; p=0.168).

Binnen de HER2+ve/HR+ subgroep bereikte van de patiënten met PIK3CA mutatie er slechts 6,5% een partiële remissie vergeleken met 30.8% in de wild type groep (p=0.005). In tegenstelling hiermee was er geen verschil in partiële remissies  (pCR) (42.9% vs. 46.1%) gerelateerd aan de PIK3CA mutatie status in de HER2+ve/HR -ve (p=0.825) groep.

In de G5 study, van 225 patiënten uit de 620 HER2+ve patiënten is er op dit moment biomateriaal beschikbaar voor een PIK3CA genotyping en een bevestiging van HER2 receptor status en AR status - hormoon receptor status. De analyses zijn nog in volle gang en later zullen de resultaten hiervan voor de trastuzumab - herceptin en lapatinib behandelde groepen worden gepubliceerd.

Interessant ook in dit verband is het studierapport: Antagonism of EGFR and HER3 Enhances the Response to Inhibitors of the PI3K-Akt Pathway in Triple-Negative Breast Cancer  te lezen dat recent , maart 2014 nog is gepubliceerd.

Hieonder verschillende abstracten gerelateerd aan bovenstaand artikel:

Neoadjuvant bevacizumab and anthracycline–taxane-based chemotherapy in 678 triple-negative primary breast cancers; results from the geparquinto study (GBG 44)†

  1. on behalf of the German Breast Group Investigators

+ Author Affiliations

  1. 1Department of Obstetrics and Gynaecology, University of Rostock, Rostock
  2. 2German Breast Group, Neu-Isenburg
  3. 3Department of Obstetrics and Gynaecology, University Schleswig-Holstein, Campus Kiel
  4. 4Department of Senology, Luisen-Hospital, Düsseldorf
  5. 5Department of Obstetrics and Gynaecology, University of Erlangen, Erlangen
  6. 6Department of Oncology, Bethanien-Hospital, Frankfurt am Main
  7. 7Department of Obstetrics and Gynaecology, University of Magdeburg
  8. 8Gynaeco-Oncological Practice, Hannover
  9. 9Breast Centre, Elisabeth Hospital, Kassel
  10. 10Department of Senology, Rotkreuz-Klinikum, München
  11. 11Department of Obstetrics and Gynaecology, University of Ulm, Ulm
  12. 12Department of Obstetrics and Gynaecology, University of Mainz, Mainz
  13. 13Department of Obstetrics and Gynaecology, Hospital Offenbach, Offenbach
  14. 14St. Johannes Hospital, Dortmund
  15. 15Department of Obstetrics and Gynaecology, Sankt Gertrauden Hospital, Berlin, Germany
  16. 16Department of Senology, Kantonsspital, Sankt Gallen, Switzerland
  17. 17Department of Obstetrics and Gynaecology, Heinrich-Heine University, Düsseldorf
  18. 18Department of Senology, Hospital, Rheinfelden
  19. 19Department of Obstetrics and Gynaecology, Helios Hospital Berlin-Buch, Berlin, Germany
  1. ↵*Correspondence to: Dr Gunter von Minckwitz, German Breast Group, GBG Forschungs GmbH, Martin-Behaim-Str. 12, 63263 Neu-Isenburg, Germany. Tel: +49-6102-7480-426-418/49-6102-7480-426-111; E-mail: ggunter.vonmminckwitz@ggermanbbreastggroup.de
  • Received February 20, 2013.
  • Revision received July 3, 2013.
  • Accepted July 18, 2013.

Abstract

Background We evaluated the pathological complete response (pCR) rate after neoadjuvant epirubicin, (E) cyclophosphamide (C) and docetaxel containing chemotherapy with and without the addition of bevacizumab in patients with triple-negative breast cancer (TNBC).

Patients and methods Patients with untreated cT1c-4d TNBC represented a stratified subset of the 1948 participants of the HER2-negative part of the GeparQuinto trial. Patients were randomized to receive four cycles EC (90/600 mg/m2; q3w) followed by four cycles docetaxel (100 mg/m2; q3w) each with or without bevacizumab (15 mg/kg; q3w) added to chemotherapy.

Results TNBC patients were randomized to chemotherapy without (n = 340) or with bevacizumab (n = 323). pCR (ypT0 ypN0, primary end point) rates were 27.9% without and 39.3% with bevacizumab (P = 0.003). According to other pCR definitions, the addition of bevacizumab increased the pCR rate from 30.9% to 41.8% (ypT0 ypN0/+; P = 0.004), 36.2% to 46.4% (ypT0/is ypN0/+; P = 0.009) and 32.9% to 43.3% (ypT0/is ypN0; P = 0.007). Bevacizumab treatment [OR 1.73, 95% confidence interval (CI) 1.23–2.42; P = 0.002], lower tumor stage (OR 2.38, 95% CI 1.24–4.54; P = 0.009) and grade 3 tumors (OR 1.68, 95% CI 1.14–2.48; P = 0.009) were confirmed as independent predictors of higher pCR in multivariate logistic regression analysis.

Conclusions The addition of bevacizumab to chemotherapy in TNBC significantly increases pCR rates.

Neoadjuvant treatments for triple-negative breast cancer (TNBC)

Neoadjuvant bevacizumab and anthracycline–taxane-based chemotherapy in 678 triple-negative primary breast cancers; results from the geparquinto study (GBG 44)†

  1. on behalf of the German Breast Group Investigators

+ Author Affiliations

  1. 1Department of Obstetrics and Gynaecology, University of Rostock, Rostock
  2. 2German Breast Group, Neu-Isenburg
  3. 3Department of Obstetrics and Gynaecology, University Schleswig-Holstein, Campus Kiel
  4. 4Department of Senology, Luisen-Hospital, Düsseldorf
  5. 5Department of Obstetrics and Gynaecology, University of Erlangen, Erlangen
  6. 6Department of Oncology, Bethanien-Hospital, Frankfurt am Main
  7. 7Department of Obstetrics and Gynaecology, University of Magdeburg
  8. 8Gynaeco-Oncological Practice, Hannover
  9. 9Breast Centre, Elisabeth Hospital, Kassel
  10. 10Department of Senology, Rotkreuz-Klinikum, München
  11. 11Department of Obstetrics and Gynaecology, University of Ulm, Ulm
  12. 12Department of Obstetrics and Gynaecology, University of Mainz, Mainz
  13. 13Department of Obstetrics and Gynaecology, Hospital Offenbach, Offenbach
  14. 14St. Johannes Hospital, Dortmund
  15. 15Department of Obstetrics and Gynaecology, Sankt Gertrauden Hospital, Berlin, Germany
  16. 16Department of Senology, Kantonsspital, Sankt Gallen, Switzerland
  17. 17Department of Obstetrics and Gynaecology, Heinrich-Heine University, Düsseldorf
  18. 18Department of Senology, Hospital, Rheinfelden
  19. 19Department of Obstetrics and Gynaecology, Helios Hospital Berlin-Buch, Berlin, Germany
  1. ↵*Correspondence to: Dr Gunter von Minckwitz, German Breast Group, GBG Forschungs GmbH, Martin-Behaim-Str. 12, 63263 Neu-Isenburg, Germany. Tel: +49-6102-7480-426-418/49-6102-7480-426-111; E-mail: ggunter.vonmminckwitz@ggermanbbreastggroup.de
  • Received February 20, 2013.
  • Revision received July 3, 2013.
  • Accepted July 18, 2013.

Abstract

Background We evaluated the pathological complete response (pCR) rate after neoadjuvant epirubicin, (E) cyclophosphamide (C) and docetaxel containing chemotherapy with and without the addition of bevacizumab in patients with triple-negative breast cancer (TNBC).

Patients and methods Patients with untreated cT1c-4d TNBC represented a stratified subset of the 1948 participants of the HER2-negative part of the GeparQuinto trial. Patients were randomized to receive four cycles EC (90/600 mg/m2; q3w) followed by four cycles docetaxel (100 mg/m2; q3w) each with or without bevacizumab (15 mg/kg; q3w) added to chemotherapy.

Results TNBC patients were randomized to chemotherapy without (n = 340) or with bevacizumab (n = 323). pCR (ypT0 ypN0, primary end point) rates were 27.9% without and 39.3% with bevacizumab (P = 0.003). According to other pCR definitions, the addition of bevacizumab increased the pCR rate from 30.9% to 41.8% (ypT0 ypN0/+; P = 0.004), 36.2% to 46.4% (ypT0/is ypN0/+; P = 0.009) and 32.9% to 43.3% (ypT0/is ypN0; P = 0.007). Bevacizumab treatment [OR 1.73, 95% confidence interval (CI) 1.23–2.42; P = 0.002], lower tumor stage (OR 2.38, 95% CI 1.24–4.54; P = 0.009) and grade 3 tumors (OR 1.68, 95% CI 1.14–2.48; P = 0.009) were confirmed as independent predictors of higher pCR in multivariate logistic regression analysis.

Conclusions The addition of bevacizumab to chemotherapy in TNBC significantly increases pCR rates.

PIK3CA Gene Mutations Make HER2 - and Hormone Receptor - positive Breast Cancers Treatment resistant

Source: San Antonio Breast Cancer Symposium

Title: PIK3CA mutation predicts resistance to anti-HER2/chemotherapy in primary HER2-positive/hormone-receptor-positive breast cancer – Prospective analysis of 737 participants of the GeparSixto and GeparQuinto studies

Authors:SibylleLoibl1, Carsten Denkert2, Andreas Schneeweis3, Stefan Paepke4, Annika Lehmann2, Mahdi Rezai5, Dirk-Michael Zahm6,Peter Sinn3, Fariba Khandan7, Holger Eidtmann8, Karel Dohnal9, Jens Huober10, Sherene Loi11, Berit Pfitzner2, Peter A Fasching12, Fabrice Andre13, Judith Lindner2, Christos Sotiriou14, Sanxing Guo1, Stephan Gade1, Valentina Nekljudova1, Michael Untch15 and Gunter von Minckwitz1,16. 1Germa Breast

Group, Neu-Isenburg; 2Charite, Berlin; 3National Center for Tumor Diseases, Heidelberg;4Klinikum Rechts der Isar der TU, München; 5Luisenkrankenhaus Düsseldorf, Düsseldorf; 6SRH Wald - Klinikum Gera, Gera; 7Agaplesion Markus Krankenhaus, Frankfurt; 8Universitätsklinikum Schleswig-Holstein, Kiel; 9Zentrum für Pathologie & Zytologie, Düsseldorf; 10Universitätsklinikum, Ulm; 11Peter MacCallum Cancer Centre, Melbourne;

12Universitätsklinikum, Erlangen; 13Institut Gustave Roussy, Villejuif; 14Institut Jules Bordet, Brussels; 15Helios Kliniken, Berlin and 16Frauenklinik Frankfurt.

Background: Phosphatidylinositol3-kinase (PI3K)/AKT pathway aberrations are common in breast cancer (BC), PIK3CA mutations being the most common. Mutations are frequently found in hot-spots located in the helical and kinase domains (exons 9 and 20).
Reported data is discrepant with regard to prognostic or predictive value of PIK3CA mutations especially in HER2+ve BC. We therefore investigated the frequency and prognostic associations of PIK3CA  mutations in HER2+ve and triple negative (TN) primary BC by treated with neoadjuvant therapy.

Methods:
We prospectively evaluated PIK3CA mutations in the 512 participants of the neoadjuvant Geparsixto (G6) study (von Minckwitz et al. ASCO 2013) and validated in 225 participants of the GeparQuinto (G5) study (Untch et al. 2012). The G6 study investigates the effect of adding carboplatin to a non-pegylated liposomal doxorubicin/taxane combination for the treatment of patients with HER2+ve and TN primary BC. All HER2+ve patients received trastuzumab and lapatinib, the TN patients received bevacizumab. The G5 study showed that trastuzumab added to EC-Doc results in a significantly higher pCR rate than lapatinib.HER2, hormone receptors (HR), and Ki67 were centrally assessed in both studies. PIK3CA was genotyped in tumor material from formalin-fixed, paraffin embedded core biopsies taken before therapy with a tumor cell content of =20% using classical Sanger sequencing of exon 9 and 20.

Results:
In the G6 study, 595 patients with HER2+ve or TN primary BC have been randomized from 09/2011 to 11/2012. Medianage was 47 years (range 21-78); most tumors were cT2 (65%); cN0 (57%); ductal invasive (93%), grade 3 (65%); within the HER2+ve group 62% were HR-positive. Currently, PIK3CA genotype is available from 512 randomized patients -240 with HER2+ve and 272 with TN disease. Overall, 13.1% were found to have at least one mutation, in HER2+ve: 19.2% and TNBC: 7.7%. PIK3CA mutations were numerically more frequent in the HER2+ve/HR+ve compared to the HER2+ve/HR-ve group: 21.5% vs 15.4% respectively (p=0.245. Overall, pCR rate was significantly lower in the PIK3CA mutant compared to wt group (22.7% vs. 43.6%; p=0.001).This effect was only significant within the HER2+ve group

This study was supported by funds from the European Commission’s Seventh RTD Framework Programmegrant number 278659 “RESPONSIFY.”

Loibl declares no conflicts of interest. # # #

chemo, avastin, lapatinib, herceptin, triple negatief, hormoongevoelig, AR, Her2, biomarker, personalised medicine, PKI3CA, borstkanker


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