SUMMARY:Genetic mechanisms leading to androgen-independent growth in advanced prostatic carcinomas (PC) are still poorly understood. Analysis of genes potentially involved in the regulation of tumor cell proliferation and apoptosis might confer better insight into this process and might lead to improved therapeutic strategies. Fluorescence in situ hybridization (FISH) analysis of dissociated nuclei with DNA probes for MYC (8q24)/#8, cyclin D1 gene (CCND1; 11q13)/#11, ERBB2 (17q13)/#17, the androgen receptor gene (AR; Xq12)/#X, and the retinoblastoma gene (RB; 13q14) was applied to formalin-fixed tissue from 63 patients with advanced PC after androgen deprivation therapy (ADT); matched tumor tissue before ADT was also available in 22 of these cases. The cut-points used were: "increased copy number," Ն 30% of all nuclei with increased FISH signals (centromere and/or gene); "amplification," Ն 15% of nuclei with "increased gene copy number." CCND1 and MYC gene "amplifications" were present before ADT in 25% and 33% of the cases, respectively; the frequency of these "amplifications" increased to 37% and 57% after ADT. Loss of the RB gene was nearly four times more frequent after ADT than before therapy (22% versus 6%). AR and ERBB2 gene "amplifications" occurred only after ADT in 36% and 30% of cases, respectively. With the exception of the AR gene, the copy number increase was low. After treatment, MYC and AR gene "amplifications" correlated with the proliferation rate (Ki-67/MIB1 index; p ϭ 0.01 and p ϭ 0.04), whereas ERBB2 "amplifications" were associated with increased apoptotic index (PCD/TUNEL; p ϭ 0.016). However, no correlation between FISH results and clinical follow-up could be established. FISH analysis of genes putatively involved in PC progression revealed characteristic patterns of aberrations in advanced PC before and after ADT. Distinct changes in gene copy number before and after therapy suggests possible involvement of these genes in the escape from androgen
The molecular mechanisms leading to androgen-independent growth in prostate cancer (PC) are poorly understood. Androgen deprivation therapy (ADT) results physiologically in a decrease in proliferation and an increase in programmed cell death (PCD)/apoptosis. The aim of our study was to get more insight into these processes in prostatic carcinomas before and after ADT. For this purpose, immunohistologic staining for the androgen receptor (AR) molecule, the Ki-67 antigen, the bcl-2 oncoprotein, the p53 protein and its physiologic effector, p21/WAF1, was performed on archival material. PCD was visualized by enzymatic detection of DNA fragmentation. Specimens from 69 PC patients after ADT were studied in correlation to histopathology and prognosis. In 42 cases, corresponding tumour tissue from the untreated primary tumours could be analysed comparatively. Before ADT, histologic grade was associated with Ki-67 index ( P < 0.0001, Spearman correlation) and PCD rate ( P < 0.05, Spearman correlation). Ki-67 index correlated with PCD rate ( P < 0.05, Spearman correlation) and p21/WAF1 expression ( P < 0.01, Fisher's exact test). p21/WAF1 expression was the only statistically significant prognostic factor for shorter survival ( P < 0.002, log-rank test). All p21/WAF1-positive cases showed high Ki-67 index and high histologic grade. After ADT, loss of AR expression was associated with high Ki-67 index, whereas histologic signs of regression correlated negatively with Ki-67 index ( P < 0.001, Pearson χ 2 test). p21/WAF1 expression increased significantly ( P < 0.02, McNemar test) and correlated with p53 accumulation ( P < 0.0001, Pearson χ 2 test). Most significant prognostic parameter after conventional ADT was high-rate p21/WAF1 expression (> 50% of tumour cells; P < 0.00001, log-rank test). This study demonstrates that p21/WAF1 overexpression before and after ADT characterizes a subgroup of advanced PC with paradoxically high proliferation rate and significantly worse clinical outcome. This finding might be clinically useful for planning therapy in these patients. © 1999 Cancer Research Campaign
Our results suggest this antigen as a suitable target for the T-cell-based immunotherapy of PCa.
BackgroundThe ETV6-NTRK3 gene fusion is present in the majority of cases of infantile fibrosarcoma (IFS) and acts as a potent oncogenic driver. We report the very rapid, complete, and sustained response of an advanced, chemotherapy-refractory, recurrent IFS to targeted treatment with the oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib.Patient and methodsA male infant born with a large congenital IFS of the tongue had the tumour surgically resected at age 4 days. Within 2 months, he developed extensive lymph node recurrence that progressed during two cycles of vincristine-doxorubicin-cyclophosphamide chemotherapy. At screening, a large right cervical mass was clinically visible. Magnetic resonance imaging (MRI) revealed bilateral cervical and axillary lymph node involvement as well as infiltration of the floor of the mouth. The largest lesion measured 5.5×4.5×4.4 cm (ca. 55 cm3). The patient started outpatient oral larotrectinib at 20 mg/kg twice daily at age 3.5 months.ResultsAfter 4 days on treatment, the parents noted that the index tumour was visibly smaller and softer. The rapid tumour regression continued over the following weeks. On day 56 of treatment, the first scheduled control MRI showed the target lesion had shrunk to 1.2×1.2×0.8 cm (ca. 0.6 cm3), corresponding to a complete response according to the Response Evaluation Criteria In Solid Tumors version 1.1. This response was maintained over subsequent follow-up visits, and on day 112 at the second control MRI the target lymph node was completely normal. At last follow-up, the disease remained in complete remission after 16 months on larotrectinib, with negligible toxicity and no safety concerns.Conclusion(s)Selective TRK inhibition by larotrectinib offers a novel, highly specific and highly effective therapeutic option for IFS carrying the characteristic ETV6-NTRK3 gene fusion. Its use should be considered when surgery is not feasible. (NCT02637687)
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