Background. The aim of this prospective study was to examine if serum concentrations of cytokines are of value in the identification of patients at risk for preterm delivery.
Methods. ...Interleukin‐1β,2,4,6,8 and tumor necrosis factor α were determined between 25 and 37 weeks of gestation in the serum of 72 consecutive patients with preterm labor, 38 patients with preterm rupture of the membranes, and 24 healthy pregnant women as a control group. Material was collected within 18 hours after hospitalization and was immediately centrifuged and shock frozen.
Results. Significantly increased serum levels were found for interleukin‐6 and ‐8 in patients with preterm labor or preterm rupture of the membranes when compared to the control group (p<0.001 and p<0.005, respectively). In patients with preterm rupture of the membranes and interleukin‐6 levels above the median of 4.0 pg/ml the delivery occurred significantly earlier than in patients with lower levels (1 versus 5.5 days; p=0.005). Patients of both pathology groups with detectable (>18 pg/ml). Interleukin‐8 levels had a shorter pregnancy duration when compared to other patients (p=0.05 for preterm labor and p=0.04 for preterm rupture of the membranes). Interleukin‐1β,2,4, and tumor necrosis factor α were not correlated with clinical outcome.
Conclusions. Increased serum interleukin‐6 and ‐8 levels are associated with a shorter interval between onset of preterm rupture of the membranes and delivery and should therefore be further evaluated for their use in clinical practice.
Previous data has shown that chemotherapy (CT)-induced amenorrhea was associated with a better DFS and OS in premenopausal patients with EBC, regardless of the hormone-receptor status (Swain et al. ...NEJM 2010 ).
740 patients (pts) aged ≤45yrs treated with anthracycline/taxane-based CT for EBC from 4 German neo-/adjuvant trials were included. Centrally assessed estradiol and follicle-stimulating hormone (FSH) in paired blood samples collected at baseline and 4 weeks after the last therapy infusion were considered. CIOF was defined as estradiol <52.2ng/L and FSH >12.4IU/l after CT for those pts with premenopausal hormone levels at baseline. 4-year DFS and OS (rate, hazard ratio (HR) and 95% confidence interval (CI)) overall and in subgroups by hormone-receptor status (positive, negative) and age (≤30, 31-35, 36-40, >40yrs) are presented.
Median follow-up was 49.6 (range 48.8-50.3) months. 4-year DFS and OS rates as well as HR overall and in subgroups are presented in the Table below. Pts with CIOF had a better DFS compared to pts without CIOF (HR=0.47, 95%CI 0.31-0.71). The DFS advantage was significant in pts with hormone-receptor positive (HR=0.38, 95%CI 0.22-0.64) EBC. A trend towards a better OS was observed only for pts with hormone-receptor positive EBC (HR=0.45, 95%CI 0.19-1.05). Within age groups, CIOF showed a statistically significant improvement in DFS only in women ≤30yrs (HR=0.21, 95%CI 0.05-0.97). No statistically significant OS benefit was observed in any of the age groups. Only pts >40yrs showed a trend towards a better OS (HR=0.35, 95%CI 0.11-1.16).Table180PDTableDFSOS4-year ratelog rank p-valueHR 95% CI4-year ratelog rank p-valueHR 95% CICIOFno CIOFCIOFno CIOFoverall (n=740)84.465.0<0.0010.47 0.31-0.7192.688.70.1800.64 0.33-1.23hormone-receptor statusnegative (n=315)79.969.70.1470.62 0.32-1.1988.989.30.8790.92 0.32-2.62positive (n=425)87.862.6<0.0010.38 0.22-0.6495.588.70.0590.45 0.19-1.05age (years)≤30 (n=62)92.869.50.0270.21 0.05-0.9795.790.80.2860.31 0.03-3.0031-35 (n=100)80.459.90.0990.49 0.21-1.1692.296.30.9451.06 0.22-5.1536-40 (n=205)81.863.50.1190.54 0.25-1.1892.784.90.4310.61 0.17-2.13>40 (n=373)85.765.00.2070.53 0.19-1.4592.481.30.0720.35 0.11-1.16
Pts with CIOF after anthracycline/taxane-based CT for EBC show a better DFS, especially in women with hormone-receptor positive EBC or younger than 30 years. The improvement in DFS translates in a survival advantage in pts with hormone-receptor positive EBC.
German Breast Group (GBG).
The study was supported by Walter Schulz Stiftung.
A. Schneeweiss: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Molecular Partner; Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): MSD Oncology; Honoraria (self): Tesaro; Honoraria (self), Travel / Accommodation / Expenses: Lilly. C. Denkert: Shareholder / Stockholder / Stock options: Sividon Diagnostics; Honoraria (self): Teva; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Amgen; Advisory / Consultancy: MSD Oncology; Advisory / Consultancy: Daiichi Sankyo; Licensing / Royalties: VMScope digital pathology software; Licensing / Royalties: Patent application: EP18209672 - cancer immunotherapy; Licensing / Royalties: Patent application EP20150702464 - therapy response; Licensing / Royalties: Patent application EP20150702464 - therapy response. M. Untch: Honoraria (institution), Non-remunerated activity/ies: Abbvie; Honoraria (institution), Non-remunerated activity/ies: Amgen GmbH; Honoraria (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (institution): BMS; Honoraria (institution), Non-remunerated activity/ies: Celgene GmbH; Honoraria (institution), Non-remunerated activity/ies: Daiji Sankyo; Honoraria (institution), Non-remunerated activity/ies: Eisai GmbH; Honoraria (institution), Non-remunerated activity/ies: Janssen Cilag; Honoraria (institution), Non-remunerated activity/ies: Lilly; Honoraria (institution), Non-remunerated activity/ies: MSD Merck; Honoraria (institution), Non-remunerated activity/ies: Mundipharma; Honoraria (institution), Non-remunerated activity/ies: Myriad Genetics; Honoraria (institution), Non-remunerated activity/ies: Odonate; Honoraria (institution), Non-remunerated activity/ies: Pfizer GmbH; Honoraria (institution): PUMA Biotechnology; Honoraria (institution), Non-remunerated activity/ies: Roche Pharma AG; Honoraria (institution), Non-remunerated activity/ies: Sanofi Aventis Deutschland GmbH; Honoraria (institution), Non-remunerated activity/ies: Sividon Diagnostics; Honoraria (institution), Non-remunerated activity/ies: TEVA Pharmaceuticals Ind Ltd; Honoraria (institution), Non-remunerated activity/ies: Novartis. P.A. Fasching: Honoraria (self), Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Biontech; Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Celgene; Honoraria (self): Daiichi-Sankyo; Honoraria (self): TEVA; Honoraria (self): AstraZeneca; Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Myelo Therapeutics; Honoraria (self): Macrogenics; Honoraria (self): Eisai; Honoraria (self): PUMA; Research grant / Funding (institution): Cepheid. F. Marmé: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Tesaro; Honoraria (self): Novartis; Honoraria (self): Amgen; Honoraria (self): PharmaMar; Honoraria (self): GenomicHealth; Honoraria (self): CureVac; Honoraria (self): EISAI; Honoraria (self): Clovis; Honoraria (self): Celgene. M. van Mackelenbergh: Honoraria (self): AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Amgen. V. Müller: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgem; Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Diichi-Sankyo; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Honoraria (self), Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Honoraria (self), Speaker Bureau / Expert testimony: Celgene; Honoraria (self), Speaker Bureau / Expert testimony: Teva; Honoraria (self), Speaker Bureau / Expert testimony: Janssen-Cilag; Honoraria (self), Advisory / Consultancy: Genomic Health; Honoraria (self), Advisory / Consultancy: Hexal; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Nektar; Research grant / Funding (institution): Seattle Genetics. S. Loibl: Research grant / Funding (institution): Roche; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Teva; Research grant / Funding (institution): Vifor; Research grant / Funding (institution): PRIME; Research grant / Funding (institution): Daiichi; Licensing / Royalties: EP14153692.0 pending. All other authors have declared no conflicts of interest.
Abemaciclib is an oral, selective cyclin-dependent kinase 4 & 6 inhibitor, approved for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast ...cancer (ABC) as monotherapy for endocrine refractory disease (US) and with endocrine therapy (ET) for initial treatment and after progression on ET. In the MONARCH 2 trial, abemaciclib + fulvestrant (F) significantly improved PFS compared to placebo (P) + F (median: 16.4 m vs 9.3 m; HR: 0.553) with a generally tolerable safety profile. Here we report the OS results of the prespecified interim.
MONARCH 2 (NCT02107703) was a global, randomized, double-blind phase III trial of abemaciclib + F or P + F in pre- or perimenopausal (with ovarian suppression) and postmenopausal women with advanced ET resistant HR+, HER2- ABC. 669 patients were randomized 2:1, stratified based on site of metastasis (visceral, bone-only, or other) and resistance to prior ET (primary vs secondary). Abemaciclib or P 150mg was dosed Q12H, and F 500mg was administered per label. The primary objective was investigator-assessed PFS. OS was a gated secondary endpoint. The boundary p-value for the interim analysis was 0.0208.
At the prespecified interim analysis, 338 deaths (77% of the planned 441 events) were observed in the ITT population with a median OS of 46.7 m for abemaciclib + F and 37.3 m for P + F (HR: 0.757; 95% CI: 0.606, 0.945; P=0.0137). These results met the predefined boundary for significance and are thus definitive. OS benefit was consistent in all stratification factors; among stratification factors, more pronounced effects were observed in subgroups of visceral disease (HR: 0.675) and primary resistance to prior ET (HR: 0.686). PFS2 (HR: 0.675; 95% CI: 0.558, 0.816) and time to chemotherapy (HR: 0.622; 95% CI: 0.499, 0.775) were also significantly improved. Safety data were consistent with known abemaciclib safety profile.
Treatment with abemaciclib plus fulvestrant provided a statistically significant and clinically meaningful median OS benefit of 9.4 months to pre- or perimenopausal and postmenopausal patients with HR+, HER2- ABC who progressed on ET with no new safety signals observed.
NCT02107703.
Scientific writing support was provided by Sarah C. Nabinger, employee of Eli Lilly and Company.
Eli Lilly and Company.
Eli Lilly and Company.
G.W. Sledge: Research grant / Funding (institution), Travel / Accommodation / Expenses: Eli Lilly and Company. M. Toi: Honoraria (self), Research grant / Funding (institution), lecture honoraria: Chugal; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Takeda; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Pfizer; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Kyowa-Hakko-Kirin; Honoraria (self), Research grant / Funding (institution), lecture honoraria: C & C Res Lab; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Talho; Research grant / Funding (institution), Officer / Board of Directors: JBCRG association; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Eisai; Honoraria (self), Research grant / Funding (institution), lecture honoraria: Dallchl-Sankyo; Honoraria (self), Research grant / Funding (institution), lecture honoraria: AstraZeneca; Honoraria (self), lecture honoraria: Eli Lilly and Company; Honoraria (self): MSD; Honoraria (self), lecture honoraria: Novartis; Honoraria (self), Honoraria for a meeting: Konica Minorta; Honoraria (self), Honoraria for a meeting: Genomic Health; Officer / Board of Directors: Organisation for Oncology and Translational Research; Officer / Board of Directors: Kyoto Breast Cancer Research Network. P. Neven: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Honoraria (institution), Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy: Roche; Research grant / Funding (self): Kom op Tegan Kanker; Honoraria (institution): Benelux. K. Inoue: Honoraria (self), Research grant / Funding (institution): Eli Lilly and Company; Honoraria (self), Honoraria (institution): Esal; Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Chugal; Research grant / Funding (institution): Dailchl Sankyo; Research grant / Funding (institution): Parexel/Puma Biotechnology; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Bayer. X. Pivot: Research grant / Funding (institution): Eli Lilly and Company. N. Masuda: Honoraria (self), Research grant / Funding (institution), Lecture fees (Honoraria): Chugai; Honoraria (self), Research grant / Funding (institution), Lecture fees (Honoraria): AstraZeneca; Honoraria (self), Research grant / Funding (institution), Lecture fees (Honoraria): Pfizer; Honoraria (self), Research grant / Funding (institution), Lecture fees (Honoraria): Eli Lilly and Company; Honoraria (self), Research grant / Funding (institution), Lecture fees (Honoraria): Eisai; Honoraria (self), Lecture fees (Honoraria): Takeda; Research grant / Funding (institution): Kyowa-Kirin; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Daiichi Sankyo; Officer / Board of Directors: Japan Breast Cancer Research Group Association. P.A. Kaufman: Honoraria (self), Research grant / Funding (institution): Eli Lilly and Company; Honoraria (self): AstraZeneca; Research grant / Funding (institution): Novartis. H. Koh: Research grant / Funding (institution): Eli Lilly and Company. E. Grischke: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Eli Lilly and Company. P.F. Conte: Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses, travel grant: Eli Lilly and Company; Research grant / Funding (institution): Roche; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self), travel grant: Celgene; Honoraria (self), travel grant: Tesaro. Y. Lu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. S. Barriga: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. K. Hurt: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. M. Frenzel: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. S.R.D. Johnston: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Puma Biotechnology; Speaker Bureau / Expert testimony: Elsal. A. Llombart-Cussac: Shareholder / Stockholder / Stock options: MedSIR; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly and Company; Honoraria (self), Research grant / Funding (institution): Celgene; Honoraria (self), Research grant / Funding (institution): Plere Fabre; Research grant / Funding (institution): Genomic Health; Research grant / Funding (institution): Puma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Non-financial support: AstraZeneca; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): ELSAI; Honoraria (self): Ferrer Incode - Agendia. All other authors have declared no conflicts of interest.
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