Kiinteiden kasvainten syöpälääkeherkkyyden ennustaminen

Vertaisarvioitu.Oikea hoito oikealle potilaalle oikeaan aikaan on yksilöllisen lääkehoidon tavoite. Saman elimen syöpäkasvaimet ovat molekyylitasolla toisistaan poikkeavia, ja viime kädessä jokainen kasvain on yksilö. Viime vuosina kasvainten molekulaarisia eroja on huomioitu yhä enemmän, mutta pääosa hoitosuosituksista pohjautuu edelleen tutkimuksiin, joissa kasvainten molekulaarista rakennetta ei ole huomioitu tai on huomioitu yksittäinen muutos. Kasvainten lääkeherkkyyden arviointiin on viime vuosina kehitetty työkaluja, joista monet ovat jo sovellettavissa käytäntöön. On myös julkaistu tutkimuksia, joissa potilaille on pystytty valitsemaan tehoava hoito kasvaimen mutaatioprofiilin perusteella. Nykyisin pieni vähemmistö kasvaimista profiloidaan. Kuitenkin esimerkiksi rinta, suolisto- ja keuhkosyöpien sekä melanoomien hoidon valinta osin mutaatioiden perusteella on jo arkipäivää.Peer reviewe

Ex vivo -mallit ja nestebiopsia yksilöllistetyssä syövänhoidossa

Vertaisarvioitu. Teema : geeniohjatun syövän hoidon työryhmä.Syövän tutkimus- ja hoitomenetelmät kehittyvät jatkuvasti yksilöllistetympään suuntaan. Syynä ovat molekyyliprofiloinnin menetelmien kehitys, siitä saatava tieto ja geenidiagnostiikkaan perustuvat lääkkeet. Hoidon valitsemiseksi tarvitaan ja käytetään yhä useammin vastetta ennakoivia biomarkkereita. Potilaskohtaiset ex vivo -syöpämallit mahdollistavat tulevaisuudessa yksilöllistetyn, systeemibiologian periaatteita hyödyntävän syövänhoidon tutkimuksen, biomarkkereiden identifioinnin ja uusien hoitostrategioiden testaamisen. Ex vivo -mallien avulla voitaneen ohjata myös suoraan hoidon valintaa, luultavasti ensin hematologisissa syöpätaudeissa. Nestebiopsiasta tehtävä molekyyliprofilointi mahdollistaa ajantasaisen geenidiagnostiikan, jolloin hoitojen aiheuttamassa evoluutiopaineessa alati tapahtuva syövän muuntuminen voidaan huomata. Jotta syövän systeemibiologisen perustutkimuksen havaintoja päästään hyödyntämään potilastyössä, tarvitaan kliiniseen työhön niveltyvää yksilöllistä syövänhoidon tutkimusta, koulutusta ja osaamista.Peer reviewe

Ex vivo -mallit ja nestebiopsia yksilöllistetyssä syövänhoidossa

Syövän tutkimus- ja hoitomenetelmät kehittyvät jatkuvasti yksilöllistetympään suuntaan. Syynä ovat molekyyliprofiloinnin menetelmien kehitys, siitä saatava tieto ja geenidiagnostiikkaan perustuvat lääkkeet. Hoidon valitsemiseksi tarvitaan ja käytetään yhä useammin vastetta ennakoivia biomarkkereita. Potilaskohtaiset ex vivo -syöpämallit mahdollistavat tulevaisuudessa yksilöllistetyn, systeemibiologian periaatteita hyödyntävän syövänhoidon tutkimuksen, biomarkkereiden identifioinnin ja uusien hoitostrategioiden testaamisen. Ex vivo -mallien avulla voitaneen ohjata myös suoraan hoidon valintaa, luultavasti ensin hematologisissa syöpätaudeissa. Nestebiopsiasta tehtävä molekyyliprofilointi mahdollistaa ajantasaisen geenidiagnostiikan, jolloin hoitojen aiheuttamassa evoluutiopaineessa alati tapahtuva syövän muuntuminen voidaan huomata. Jotta syövän systeemibiologisen perustutkimuksen havaintoja päästään hyödyntämään potilastyössä, tarvitaan kliiniseen työhön niveltyvää yksilöllistä syövänhoidon tutkimusta, koulutusta ja osaamista

Keuhkosyövän molekyylipatologinen diagnostiikka edellyttää perustietoja myös kliinikoilta

Teema : keuhkosyövän diagnostiikka ja hoito. English summaryPeer reviewe

Single Center Experience with a 4-Week 177Lu-PSMA-617 Treatment Interval in Patients with Metastatic Castration-Resistant Prostate Cancer

Background: 177Lu-PSMA-617 is a promising theragnostic treatment for metastatic castration-resistant prostate cancer (mCRPC). However, both the optimal treatment dose and interval in mCRPC and the rate of identification of responders from non-responders among possible treatment candidates are unknown. Methods: 62 men with mCRPC who were treated with 177Lu-PSMA-617 during 1/2017–2/2019 were included in the study. Treatment responses, overall survival (OS) and progression free survival (PFS) were determined. The median follow-up time was 1.4 years (IQR 0.5–2.2). Tumor volume of metastases (MTV), SUVmax and tumor lesion activity (TLA) were quantitated from pre-treatment PSMA PET/CT images together with pre-treatment PSA. Results: An average of three treatment cycles (2–5) were given within a four-week interval. PFS was 4.9 months (2.4–9.6) and OS was 17.2 months (6–26.4). There were no major adverse events reported. A significant PSA response of >50% was found in 58.7% of patients, which was significantly associated with longer OS, p < 0.004. PSA response was not associated with staging PSMA-derived parameters. Conclusions: 177Lu-PSMA-617 treatment in four-week intervals was safe and effective. Almost 60% of patients had a significant PSA response, which was associated with better OS. Pre-treatment PSA kinetics or staging PSMA PET/CT-derived parameters were not helpful in identifying treatment responders from non-responders; better biomarkers are needed to aid in patient selection.© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).fi=vertaisarvioitu|en=peerReviewed

Patterns of HER-2/neu Amplification and Overexpression in Primary and Metastatic Breast Cancer

Background: Only 25% of patients with HER-2/neu-positive metastatic breast tumors respond favorably to trastuzamab (Herceptin) treatment. We hypothesized that a high failure rate of patients on trastuzamab could result if some of the metastases were HER-2 negative and these metastases ultimately determine the course of the disease. Methods: We used tissue microarrays (TMAs) containing four samples each from 196 lymph node-negative primary tumors, 196 lymph node-positive primary tumors, and three different lymph node metastases from each lymph node-positive tumor to estimate HER-2 gene amplification by fluorescence in situ hybridization (FISH) and Her-2 protein overexpression by immunohistochemistry (IHC). Results: FISH and IHC analyses gave the same result with respect to HER-2 status for 93.7% of the tissues contained in the TMAs. Tissue samples were, therefore, considered to be HER-2 positive if they were positive for either HER-2 DNA amplification or Her-2 protein expression and HER-2 negative if both FISH and IHC gave a negative result. The HER-2 status of lymph node-positive primary tumors was maintained in the majority of their metastases. For HER-2-positive primary tumors, 77% (95% confidence interval [CI] = 59% to 90%) had entirely HER-2-positive metastases, 6.5% (95% CI = 8% to 21%) had entirely HER-2-negative metastases, and 16.3% (95% CI = 5% to 34%) had a mixture of HER-2-positive and HER-2-negative metastases. For HER-2-negative primary tumors, 95% (95% CI = 88% to 98%) had metastases that were entirely negative for HER-2. Conclusions: Our data suggest that differences in HER-2 expression between primary tumors and their lymph node metastases cannot explain the high fraction of nonresponders to trastuzamab therap

Detecting Activation of Ribosomal Protein S6 Kinase by Complementary DNA and Tissue Microarray Analysis

Background: Studies by comparative genomic hybridization (CGH) have shown that chromosomal region 17q23 is amplified in up to 20% of primary breast cancers. We used microarray analyses to measure the expression levels of genes in this region and to explore their prognostic importance. Methods: A microarray that contained 4209 complementary DNA (cDNA) clones was used to identify genes that are overexpressed in the MCF-7 breast cancer cell line as compared with normal mammary tissue. Fluorescence in situ hybridization was used to analyze the copy number of one overexpressed gene, ribosomal protein S6 kinase (S6K), and to localize it to the 17q23 region. Northern and western blot analyses were used to measure S6K gene and protein expression, and an enzymatic assay was used to measure S6K activity. Tumor tissue microarray analysis was used to study amplification of S6K and the HER-2 oncogene, another 17q-linked gene, and the relationship between amplification and prognosis was analyzed. The Kaplan-Meier method was used for data analysis, and the log-rank test was used for statistical analysis. All P values are two-sided. Results: S6K was amplified and highly overexpressed in MCF-7 cells relative to normal mammary epithelium, and protein expression and enzyme activity were increased. S6K was amplified in 59 (8.8%) of 668 primary breast tumors, and a statistically significant association between amplification and poor prognosis (P = .0021) was observed. Amplification of both S6K and HER-2 implied particularly poor survival (P = .0001). Conclusions: The combination of CGH information with cDNA and tissue microarray analyses can be used to identify amplified and overexpressed genes and to evaluate the clinical implications of such genes and genomic rearrangements. S6K is likely to be one of the genes at 17q23 that is amplified during oncogenesis and may adversely affect the prognosis of patients with this amplificatio

Ex vivo drug screening informed targeted therapy for metastatic parotid squamous cell carcinoma

The purpose of ex vivo drug screening in the context of precision oncology is to serve as a functional diagnostic method for therapy efficacy modeling directly on patient-derived tumor cells. Here, we report a case study using integrated multiomics ex vivo drug screening approach to assess therapy efficacy in a rare metastatic squamous cell carcinoma of the parotid gland. Tumor cells isolated from lymph node metastasis and distal subcutaneous metastasis were used for imaging-based single-cell resolution drug screening and reverse-phase protein array-based drug screening assays to inform the treatment strategy after standard therapeutic options had been exhausted. The drug targets discovered on the basis of the ex vivo measured drug efficacy were validated with histopathology, genomic profiling, and in vitro cell biology methods, and targeted treatments with durable clinical responses were achieved. These results demonstrate the use of serial ex vivo drug screening to inform adjuvant therapy options prior to and during treatment and highlight HER2 as a potential therapy target also in metastatic squamous cell carcinoma of the salivary glands

Hormone Therapy Failure in Human Prostate Cancer: Analysis by Complementary DNA andTissue Microarrays

BACKGROUND: The molecular mechanisms underlying the progression of prostate cancer during hormonal therapy have remained poorly understood. In this study, we developed a new strategy for the identification of differentially expressed genes in hormone-refractory human prostate cancer by use of a combination of complementary DNA (cDNA) and tissue microarray technologies. METHODS: Differences in gene expression between hormone-refractory CWR22R prostate cancer xenografts (human prostate cancer transplanted into nude mice) and a xenograft of the parental, hormone-sensitive CWR22 strain were analyzed by use of cDNA microarray technology. To validate the data from cDNA microarrays on clinical prostate cancer specimens, a tissue microarray of specimens from 26 prostates with benign prostatic hyperplasia, 208 primary prostate cancers, and 30 hormone-refractory local recurrences was constructed and used for immunohistochemical detection of protein expression. RESULTS: Among 5184 genes surveyed with cDNA microarray technology, expression of 37 (0.7%) was increased more than twofold in the hormone-refractory CWR22R xenografts compared with the CWR22 xenograft; expression of 135 (2.6%) genes was reduced by more than 50%. The genes encoding insulin-like growth factor-binding protein 2 (IGFBP2) and 27-kd heat-shock protein (HSP27) were among the most consistently overexpressed genes in the CWR22R tumors. Immunohistochemical analysis of tissue microarrays demonstrated high expression of IGFBP2 protein in 100% of the hormone-refractory clinical tumors, in 36% of the primary tumors, and in 0% of the benign prostatic specimens (two-sided P = .0001). Overexpression of HSP27 protein was demonstrated in 31% of the hormone-refractory tumors, in 5% of the primary tumors, and in 0% of the benign prostatic specimens (two-sided P = .0001). CONCLUSIONS: The combination of cDNA and tissue microarray technologies enables rapid identification of genes associated with progression of prostate cancer to the hormone-refractory state and may facilitate analysis of the role of the encoded gene products in the pathogenesis of human prostate cance

Ex vivo assessment of targeted therapies in a rare metastatic epithelial–myoepithelial carcinoma

Epithelial–myoepithelial carcinoma (EMC) is a rare subtype of salivary gland neoplasms. Since the initial description of the cancer, just over 300 cases have been reported. EMCs occupy a biphasic cellular differentiation-state defined by the constitution of two cell types representing epithelial and myoepithelial lineages, yet the functional consequence of the differentiation-state heterogeneity with respect to therapy resistance of the tumors remains unclear. The reported local recurrence rate of the cases is approximately 30%, and while distant metastases are rare, a significant fraction of these cases are reported to receive no survival benefit from radio- or chemotherapy given in addition to surgery. Moreover, no targeted therapies have been reported for these neoplasms. We report here the first use and application of ex vivo drug screening together with next generation sequencing to assess targeted treatment strategies for a rare metastatic epithelial–myoepithelial carcinoma. Results of the ex vivo drug screen demonstrate significant differential therapeutic sensitivity between the epithelial and myoepithelial intra-tumor cell lineages suggesting that differentiation-state heterogeneity within epithelial–myoepithelial carcinomas may present an outlet to partial therapeutic responses to targeted therapies including MEK and mTOR inhibitors. These results suggest that the intra-tumor lineage composition of EMC could be an important factor to be assessed when novel treatments are being evaluated for management of metastatic EMC