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Biomarker für die individualisierte Behandlung solider Tumoren

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Abstract

Zusammenfassung In den letzten Jahren wurde durch Grundlagenforschung und translationale Forschung in der Onkologie eine Reihe von Biomarkern identifiziert, die für Diagnostik, Staging, Prognoseabschätzung und als Ansatzpunkte für individualisierte Therapien potentiellen klinischen Wert haben. Einige dieser Marker sind bereits in die klinische Praxis eingeführt, andere werden derzeit im Rahmen wissenschaftlicher Programme an Comprehensive Cancer Centers und innerhalb von Studiengruppen in ihrer Anwendung erprobt. Dieser Beitrag gibt einen Überblick über bereits klinisch etablierte Biomarker bei soliden Krebserkrankungen und einen Ausblick auf Kandidaten, die an der Schwelle zur breiten klinischen Anwendung stehen.

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Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme of 5-fluorouracil (5-FU) catabolism. We report lymphocytic DPD data concerning a group of 53 patients (23 men, 30 women, mean age 58, range 36-73), treated by 5-FU-based chemotherapy in different French institutions and who developed unanticipated 5-FU-related toxicity. Lymphocyte samples (standard collection procedure) were sent to us for DPD determination (biochemical method). Among the whole group of 53 patients, 19 had a significant DPD deficiency (DD; below 150 fmol min(-1) mg(-1) protein, i.e. less than 70% of the mean value observed from previous population study). There was a greater majority of women in the DD group (15 out of 19, 79%) compared with the remaining 34 patients (15 out of 34, 44%, P<0.014). Toxicity was often severe, leading to patient death in two cases (both women). The toxicity score (sum of WHO grading, theoretical range 0-20) was twice as high in patients with marked DD (below 100 pmol min(-1) mg(-1) protein, n = 11, mean score = 13.2) compared with patients with moderate DD (between 150 and 100 pmol min(-1) mg(-1) protein, n = 8, mean score = 6.8), P = 0.008. In the DD group, there was a high frequency of neurotoxic syndromes (7 out of 19, 37%). The two deceased patients both had severe neurotoxicity. The occurrence of cardiac toxicity was relatively rare (1 out of 19, 5%). These data suggest that women are particularly prone to DPD deficiency and allow a more precise definition of the DD toxicity profile.
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To compare the efficacy and tolerability of anastrozole (Arimidex; AstraZeneca, Wilmington, DE, and Macclesfield, United Kingdom) with that of tamoxifen as first-line therapy for advanced breast cancer (ABC) in postmenopausal women. This randomized, double-blind, multicenter study evaluated the efficacy of anastrozole 1 mg once daily relative to tamoxifen 20 mg once daily in patients with tumors that were hormone receptor-positive or of unknown receptor status who were eligible for endocrine therapy. The primary end points were time to progression (TTP), objective response (OR), and tolerability. A total of 668 patients (340 in the anastrozole arm and 328 in the tamoxifen arm) were randomized to treatment and followed-up for a median of 19 months. Median TTP was similar for both treatments (8.2 months in patients who received anastrozole and 8.3 months in patients who received tamoxifen). The tamoxifen:anastrozole hazards ratio was 0.99 (lower one-sided 95% confidence limit, 0.86), demonstrating that anastrozole was at least equivalent to tamoxifen. Anastrozole was also as effective as tamoxifen in terms of OR (32.9% of anastrozole and 32.6% of tamoxifen patients achieved a complete response [CR] or partial response [PR]). Clinical benefit (CR + PR + stabilization of > or = 24 weeks) rates were 56.2% and 55.5% for patients receiving anastrozole and tamoxifen, respectively. Both treatments were well tolerated. However, incidences of thromboembolic events and vaginal bleeding were reported in fewer patients treated with anastrozole than with tamoxifen (4.8% v 7.3% [thromboembolic events] and 1.2% v 2.4% [vaginal bleeding], respectively). Anastrozole satisfied the predefined criteria for equivalence to tamoxifen. Together with the lower observed incidence of thromboembolic events and vaginal bleeding, these findings indicate that anastrozole should be considered as first-line therapy for postmenopausal women with ABC.
Article
Overexpression of the excision repair cross-complementing 1 (ERCC1) gene, which is crucial in the repair of cisplatin (CDDP)-DNA adducts, is reported to negatively influence the effectiveness of CDDP-based therapy for gastric and ovarian cancers. Recent evidence indicates that Gemcitabine (Gem) may modulate ERCC1 nucleotide excision repair activity, and down-regulation of DNA repair activity by ERCC1 antisense RNA reportedly inhibits synergism of CDDP/Gem. We investigated whether ERCC1 mRNA expression levels were associated with clinical outcomes after treatment with a combination Gem/CDDP regimen for patients with advanced stage non-small cell lung cancer (NSCLC). Response and survival were correlated with the level of ERCC1 expression in 56 patients with advanced (stage IIIb or IV) NSCLC treated as part of a multicenter randomized trial with Gem 1250 mg/m(2) days 1 and 8 plus CDDP 100 mg/m(2) on day 1 every 3 weeks. mRNA was isolated from paraffin-embedded pretreatment primary tumor specimens, and relative expression levels of ERCC1/beta-actin were measured using a quantitative reverse transcription-PCR (Taqman) system. ERCC1 expression was detectable in all tumors. There were no significant differences in ERCC1 levels by gender, age, performance status, weight loss, or tumor stage. The overall response rate was 44.7%. There were no significant associations between ERCC1 expression and response. Median overall survival was significantly longer in patients with low ERCC1 expression tumors (61.6 weeks; 95% confidence interval, 42.4-80.7 weeks) compared to patients with high expression tumors (20.4 weeks, 95% confidence interval, 6.9-33.9 weeks). ERCC1 expression, Eastern Cooperative Oncology Group performance status, and presence of weight loss were significant prognostic factors for survival in a Cox proportional hazards multivariable analysis. These data suggest that ERCC1 expression is a predictive factor for survival after CDDP/Gem therapy in advanced NSCLC. Although there was a trend toward decreased response with high ERCC1 mRNA levels, this difference failed to reach statistical significance. This result may reflect the impact of Gem and the requirement for ERCC1 expression for CDDP/Gem synergism or may be attributable to the relatively small patient sample size in this study. Prospective studies of ERCC1 as a predictive marker for activity of CDDP-based regimens in NSCLC are warranted.
College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer
  • Ac Wolff
  • Me Hammond
  • Schwartz
  • Jn
Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer
  • R V Lord
  • J Brabender
  • D Gandara
  • R.V. Lord
Amplification of HER-2/neu and topoisomerase IIalpha in primary and metastatic breast cancer
  • M Tanner
  • P Jarvinen
  • J Isola
  • M. Tanner
American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer
  • A C Wolff
  • M E Hammond
  • J N Schwartz
  • A.C. Wolff