Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study.

BACKGROUND: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. PATIENTS AND METHODS: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. RESULTS: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. CONCLUSION: Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.

[Genetic risk factors for sporadic germ cell testicular tumors].

INTRODUCTION: Approximately 95% of all testicular cancers are testicular germ cell tumors (GCTTs), represented by seminoma and nonseminoma germ cell testicular cancer. There is a hypothesis that the formation of GCTTs begins in early embryogenesis being a part of testicular dysgenesis syndrome (TDS). AIM: To determine the role of genetic factors in the development of GCTTs. MATERIALS AND METHODS: We studied the frequency of alleles and genotypes KITLG (rs995030, rs1508595), SPRY4 (rs4624820, rs6897876) and BAK1 (rs210138) in 97 fertile men (control), and 73 patients with GCTTs (34 seminoma and 39 nonseminoma). RESULTS: GCTTs were statistically significantly associated with KITLG rs1508595 gene (p=0.0003 for allele G, p=0.0014 for genotype GG), and with rs995030 gene (p=0.0031 for genotype GG). When comparing patients with seminoma and control group, statistically significant differences were found for SPRY4 rs4624820 (p=0.0226 for the A and p=0.04 for the AA), for KITLG rs995030 (p=0.0375 for the G and p=0.0282 for GG), rs1508595 (p=0.0306 for G), for BAK1 rs210138 (p=0.0329 for the G and p=0.0219 for the GG). When comparing patients with nonseminoma and fertile men, statistically significant differences were found only for KITLG rs1508595 (p=0.0005 for the G and p=0.0021 for the GG). There was no statistically significant difference between the allele and genotype frequencies of the investigated genes from seminoma and nonseminoma GCTTs patients. However, these groups differed statistically significantly when genotype combinations of the three genes were investigated (p=0,029; OR 3,709 [1.147-11.99]). The combination of genotypes of the three genes was found to increase the risk of GCTTs by 6.5 times (p=0.0005; OR 6.526 [2.078-20.5], and the risk for seminoma was over 12-fold (p<0.0001; OR 12,68 [3,731-43,11]. CONCLUSION: A comprehensive study of genotypes associated with GCTTs in patients with manifested TDS can be used for risk stratification to identify and follow-up high-risk patients, develop approaches to family counseling and treatment, which is the basis for predictive medicine.

Paclitaxel+BEP (T-BEP) regimen as induction chemotherapy in poor prognosis patients with nonseminomatous germ cell tumors: a phase II study.

OBJECTIVES: To evaluate paclitaxel, bleomycin, etoposide, and cisplatin (T-BEP) in patients with poor-prognosis nonseminomatous germ cell tumor (NSGCT). Paclitaxel is an active treatment of nonseminomatous germ cell tumors. METHODS: The present study was an open-label, single-center, Phase II study. Chemotherapy-naive patients received T-BEP (paclitaxel 175 mg/m2 [day 2], cisplatin 20 mg/m2 [days 1-5], etoposide 100 mg/m2 [days 1-5], bleomycin 30 IU [days 1, 3, and 5]), and granulocyte colony-stimulating factor 300 µg (days 6-10). The number of cycles (range 4-6) was dependent on the normalization of tumor markers. Secondary resection was planned for patients with tumor marker-negative partial remission. Assessments included radiologic response, tumor markers, and safety. The primary endpoint was progression-free survival (PFS) 1 year after chemotherapy. RESULTS: Of 51 patients, 49 completed chemotherapy and were evaluable for response: 12 (25%) had a complete response, 29 (59%) were marker-negative (tumor marker normalization) and 3 (6%) were marker-positive (tumor marker decrease for ≥1 month) incomplete responders, and 5 (10%) had progressive disease. A total of 37 patients underwent secondary resection. After the treatment of 27 patients, an unplanned analysis showed inappropriate toxicity at cycle 1 (grade 3-4 infection [6 patients] resulting in 2 toxic deaths), which led to treatment modification (BEP [cycle 1], T-BEP [subsequent cycles]), with no further toxic deaths observed. Grade 3-4 adverse events included neutropenia (71%), febrile neutropenia (33%), and infection (14%). During the first year after chemotherapy, 1 patient was lost to follow-up, and 21 patients relapsed. The PFS rate at 1 year after chemotherapy was 58% (29 of 50 patients). CONCLUSIONS: T-BEP did not improve PFS in patients with poor-prognosis NSGCT. The administration of T-BEP from cycle 1 resulted in excessive toxicity but was administered safely from cycle 2.

A prognostic model in patients treated for metastatic gastric cancer with second-line chemotherapy.

BACKGROUND: This retrospective study was carried out to evaluate the prognostic significance of clinical factors in patients treated for metastatic gastric cancer with second-line chemotherapy. PATIENTS AND METHODS: We evaluated the prognostic significance of various clinical factors in 126 patients, who were treated with second-line chemotherapy. RESULTS: Median progression-free and overall survival (OS) for second-line chemotherapy were 3.3 and 5.3 months, respectively, with an overall response rate of 11.1%. Multivariate analysis identified three independent prognostic factors: performance status: Eastern Cooperative Oncology Group zero to one [hazard ratio (HR) 2.3, 95% confidence interval (CI) 1.7-5.4], hemoglobin (Hb) level: >/=10 g/dl (HR 2.2, 95% CI 2.1-2.4) and time-to-progression (TTP) under first-line therapy: >/=5 months (HR 0.5, 95% CI 0.3-0.8). From the obtained data, a prognostic index was constructed, dividing the patients into three risk groups: good (n = 40), intermediate (n = 36) and poor risk group (n = 56). The median survival for good, intermediate and poor risk groups were 13.5, 6.0 and 2.9 months, respectively, whereas the 1-year OS rates were 50.2%, 14.2% and 2.6%, respectively (P = 0.00001). CONCLUSIONS: With inadequate data from randomized controlled trials at the moment, our report indicates that second-line chemotherapy is effective and beneficial in patients with good performance status, higher Hb level along with higher TTP under first-line therapy.