There is a clinical need to predict sensitivity of metastatic hormone receptor-positive and HER2-negative (HR+/HER2−) breast cancer to endocrine therapy, and targeted RNA sequencing (RNAseq) offers diagnostic potential to measure both transcriptional activity and functional mutation. We developed the SET ER/PR index to measure gene expression microarray probe sets that were correlated with hormone receptors ( ESR1 and PGR ) and robust to preanalytical and analytical influences. We tested SET ER/PR index in biopsies of metastastic HR+/HER2− breast cancer against the treatment outcomes in 140 patients. Then we customized the SET ER/PR assay to measure 18 informative, 10 reference transcripts, and sequence the ligand-binding domain (LBD) of ESR1 using droplet-based targeted RNAseq, and tested that in residual RNA from 53 patients. Higher SET ER/PR index in metastatic samples predicted longer PFS and OS when patients received endocrine therapy as next treatment, even after adjustment for clinical-pathologic risk factors (PFS: HR 0.534, 95% CI 0.299 to 0.955, p = 0.035; OS: HR 0.315, 95% CI 0.157 to 0.631, p = 0.001). Mutated ESR1 LBD was detected in 8/53 (15%) of metastases, involving 1−98% of ESR1 transcripts (all had high SET ER/PR index). A signature based on probe sets with good preanalytical and analytical performance facilitated our customization of an accurate targeted RNAseq assay to measure both phenotype and genotype of ER-related transcription. Elevated SET ER/PR was associated with prolonged sensitivity to endocrine therapy in patients with metastatic HR+/HER2− breast cancer, especially in the absence of mutated ESR1 transcript.

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BACKGROUND.The objective of this study was to determine the prognostic variables that influence response and survival in patients with metastatic neuroendocrine tumors who are treated with hepatic arterial embolization (HAE) or chemoembolization (HACE). METHODS.Patients with metastatic neuroendocrine tumors who underwent HAE or HACE were included in this retrospective study. Follow-up imaging studies were compared with baseline imaging to determine the radiologic response. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to assess the prognostic variables that affected response and survival. RESULTS.The study included 69 patients with carcinoid tumors and 54 patients with pancreatic islet cell carcinomas. Patients who had carcinoid tumors had a higher response rate (66.7% vs. 35.2%; P ϭ 0.0001) and had longer PFS (22.7 mos vs. 16.1 mos; P ϭ 0.046) and OS (33.8 mos vs. 23.2 mos; P ϭ 0.012) compared with patients who had islet cell carcinomas. For patients with carcinoid tumors, multivariate analysis identified male gender as the only independent risk factor for poor survival (P ϭ 0.05). Octreotide was predictive marginally for PFS (P ϭ 0.06). Patients who were treated with HAE had a higher response rate than patients who were treated with HACE (P ϭ 0.004). For patients with islet cell carcinoma, an intact primary tumor, Ն 75% liver involvement, and extrahepatic metastases were associated with reduced OS in the univariate analysis; the presence of bone metastases was the only risk factor (P ϭ 0.031) in the multivariate analysis. Patients who were treated with HACE had a prolonged OS (31.5 mos vs. 18.2 mos) and improved response (50% vs. 25%) compared with patients who were treated with HAE, although the differences did not reach statistical significance. CONCLUSIONS.Patients with carcinoid tumors had better outcomes than patients with islet cell carcinomas. The addition of intraarterial chemotherapy to HAE did not improve the outcome of patients with carcinoid tumors, but it seemed to benefit patients with islet cell carcinomas. In patients who had carcinoid tumors, male gender predicted a poor outcome, and a trend toward prolonged PFS was observed in patients who received concomitant octreotide.An intact primary tumor, extensive liver disease, and bone metastases were associated with reduced survival in patients with islet cell carcinomas. Cancer

Radioembolization with 90Y-microspheres to the whole liver, or lobe with single or multiple fractions are safe and produce high response rates, even with extensive tumor replacement of normal liver and/or heavy pretreatment. The acute and delayed toxicity was very low without a treatment related grade 4 acute event or radiation induced liver disease in this modest-sized cohort. The significant objective response suggests that further investigation of this approach is warranted.

Species of Clostridium bacteria are notable for their ability to lyse tumor cells growing in hypoxic environments. We show that an attenuated strain of Clostridium novyi (C. novyi-NT) induces a microscopically precise, tumor-localized response in a rat orthotopic brain tumor model after intratumoral injection. It is well known, however, that experimental models often do not reliably predict the responses of human patients to therapeutic agents. We therefore used naturally occurring canine tumors as a translational bridge to human trials. Canine tumors are more like those of humans because they occur in animals with heterogeneous genetic backgrounds, are of host origin, and are due to spontaneous rather than engineered mutations. We found that intratumoral injection of C. novyi-NT spores was well tolerated in companion dogs bearing spontaneous solid tumors, with the most common toxicities being the expected symptoms associated with bacterial infections. Objective responses were observed in 6 of 16 dogs (37.5%), with three complete and three partial responses. On the basis of these encouraging results, we treated a human patient who had an advanced leiomyosarcoma with an intratumoral injection of C. novyi-NT spores. This treatment reduced the tumor within and surrounding the bone. Together, these results show that C. novyi-NT can precisely eradicate neoplastic tissues and suggest that further clinical trials of this agent in selected patients are warranted.

Management of hepatic malignancies is a ubiquitous medical problem. Surgical resection of primary or metastatic liver cancer, with or without adjuvant chemotherapy, is the most effective method for enhancing survival; however, hepatic malignancies in the vast majority of patients are unresectable both at initial manifestation and at recurrence. In these patients, palliative cytoreductive therapies may help to retard tumor progression and therefore favorably alter the course of the disease. Since hepatic neoplasms are principally supplied by the hepatic artery, various arterially delivered cytotoxic agents have been developed to achieve these objectives. Recently, the Food and Drug Administration approved the transarterial administration of yttrium-90 microspheres for liver-directed therapy. Effective use of these devices requires knowledge of the accumulated clinical experience and a dedicated multidisciplinary effort to ensure optimal outcomes and avoid therapy-specific life-threatening complications.

Background While the incorporation of research biopsies into clinical trials is increasing, limited information is available on how study protocols and informed consents integrate and describe their use. Methods All therapeutic clinical trials where image-guided research biopsies were performed from January 1, 2005 to October 1, 2010 were identified from an Interventional Radiology database. Data from study protocols and informed consents was extracted and analyzed. Procedural complications were recorded. Results A total of 57 clinical trials were identified, of which 38 (67%) contained at least one mandatory biopsy. Analysis of the research biopsy tumor tissue was a study endpoint in 95% of trials. The primary indication for research biopsy was for integral biomarker analysis in 32% and for correlative science in 68% of trials. A statistical analytic plan for the correlative science research biopsy tumor tissue was mentioned in 26%, described as exploratory in 51% and not mentioned in 23% of trials. For studies with mandatory biopsies, “biopsy” was an eligibility criterion in 71% of trials and a statistical justification for the research biopsy sample size was present in 50% of trials. 745 research biopsies were performed on 576 patients. The overall and major complication rates were 5.2% (39/745) and 0.8% (6/745), respectively. Complication rates for intra-thoracic and abdominal/pelvic solid organ biopsies were 17.1% (36/211) and 1.6% (3/189), respectively. Site stratified research biopsy-related risks were discussed in 5 consents. Conclusion A better representation of the risks and benefits of research biopsies in study protocols and informed consents is needed.