Stephen B. Solomon

Integrative clinical genomics of advanced prostate cancer

Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals.

Rebiopsy of Lung Cancer Patients with Acquired Resistance to EGFR Inhibitors and Enhanced Detection of the T790M Mutation Using a Locked Nucleic Acid-Based Assay

Background: The epidermal growth factor receptor (EGFR) mutation T790M is reported in approximately 50% of lung cancers with acquired resistance to EGFR inhibitors and is a potential prognostic and predictive biomarker. Its assessment can be challenging due to limited tissue availability and underdetection at low mutant allele levels. Here, we sought to determine the feasibility of tumor rebiopsy and to more accurately assess the prevalence of the T790M using a highly sensitive locked nucleic acid (LNA) PCR/sequencing assay. MET amplification was also analyzed. Methods: Patients with acquired resistance were rebiopsied and samples were studied for sensitizing EGFR mutations. Positive cases were evaluated for T790M using standard PCR-based methods and a subset were re-evaluated with an LNA-PCR/sequencing method with an analytical sensitivity of approximately 0.1%. MET amplification was assessed by FISH. Results: Of 121 patients undergoing tissue sampling, 104 (86%) were successfully analyzed for sensitizing EGFR mutations. Most failures were related to low tumor content. All patients (61/61) with matched pretreatment and resistance specimens showed concordance for the original sensitizing EGFR mutation. Standard T790M mutation analysis on 99 patients detected 51(51%) mutants. Retesting of 30 negative patients by the LNA-based method detected 11 additional mutants for an estimated prevalence of 68%. MET was amplified in 11% of cases (4/37). Conclusions: The re-biopsy of lung cancer patients with acquired resistance is feasible and provides sufficient material for mutation analysis in most patients. Using high sensitivity methods, the T790M is detected in up to 68% of these patients. Clin Cancer Res; 17(5); 1169–80. ©2011 AACR.

Image-guided Tumor Ablation: Standardization of Terminology and Reporting Criteria—A 10-Year Update

Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes. Online supplemental material is available for this article .

Ablation of Perivascular Hepatic Malignant Tumors with Irreversible Electroporation

BACKGROUND Ablation is increasingly used to treat primary and secondary liver cancer. Ablation near portal pedicles and hepatic veins is challenging. Irreversible electroporation (IRE) is a new ablation technique that does not rely on heat and, in animals, appears to be safe and effective when applied near hepatic veins and portal pedicles. This study evaluated the safety and short-term outcomes of IRE to ablate perivascular malignant liver tumors. STUDY DESIGN A retrospective review of patients treated with IRE between January 1, 2011 and November 2, 2011 was performed. Patients were selected for IRE when resection or thermal ablation was not indicated due to tumor location. Treatment outcomes were classified by local, regional, and systemic recurrence and complications. Local failure was defined as abnormal enhancement at the periphery of an ablation defect on post-procedure contrast imaging. RESULTS Twenty-eight patients had 65 tumors treated. Twenty-two patients (79%) were treated via an open approach and 6 (21%) were treated percutaneously. Median tumor size was 1 cm (range 0.5 to 5 cm). Twenty-five tumors were <1 cm from a major hepatic vein; 16 were <1 cm from a major portal pedicle. Complications included 1 intraoperative arrhythmia and 1 postoperative portal vein thrombosis. Overall morbidity was 3%. There were no treatment-associated mortalities. At median follow-up of 6 months, there was 1 tumor with persistent disease (1.9%) and 3 tumors recurred locally (5.7%). CONCLUSIONS This early analysis of IRE treatment of perivascular malignant hepatic tumors demonstrates safety for treating liver malignancies. Larger studies and longer follow-up are necessary to determine long-term efficacy.

Long-term oncological and overall outcomes of percutaneous radio frequency ablation in high risk surgical patients with a solitary small renal mass.

PURPOSE We present long-term outcomes in patients receiving RFA for solitary small renal masses. MATERIALS AND METHODS We reviewed the overall oncological and survival outcomes of patients with a solitary renal mass treated with radio frequency ablation in whom it had been at least 40 months since treatment. Patients were offered radio frequency ablation due to the high risk of surgical management and surgeon preference. Followup consisted of serum creatinine measurement, physical examination and serial contrast enhanced computerized tomography or magnetic resonance imaging. RESULTS The 31 patients received a total of 34 radio frequency ablation treatments to a 1.0 to 4.0 cm solitary renal mass (median 2.0). Mean followup in survivors was 61.6 months (median 62.4, range 41 to 80). There was 1 primary treatment failure, which was successfully retreated. There were 3 recurrences 7, 13 and 31 months after radio frequency ablation, respectively. The overall recurrence-free survival rate was 90.3%. There was a 100% metastasis-free and disease specific survival rate in the cohort. Overall patient survival was 71.0% since 9 died of nonrenal cell carcinoma causes. Of the 31 patients 18 had pathologically confirmed renal cell carcinoma. In these 18 cases the actuarial disease specific, metastasis-free, recurrence-free and overall survival rates were 100%, 100%, 79.9% and 58.3%, respectively, at a mean of 57.4 months of followup. In the entire cohort the difference between the pretreatment and the last known serum creatinine level was 0.15 mg/dl (p = 0.06). CONCLUSIONS In patients who have limited life expectancy or are high risk surgical candidates radio frequency ablation provides reasonable long-term oncological control and it may have a role in the management of small renal masses. Meticulous long-term followup is required in patients receiving radio frequency ablation.

Local Therapy with Continued EGFR Tyrosine Kinase Inhibitor Therapy as a Treatment Strategy in EGFR-Mutant Advanced Lung Cancers That Have Developed Acquired Resistance to EGFR Tyrosine Kinase Inhibitors

Background: Development of acquired resistance limits the utility of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for the treatment of EGFR-mutant lung cancers. There are no accepted targeted therapies for use after acquired resistance develops. Metastasectomy is used in other cancers to manage oligometastatic disease. We hypothesized that local therapy is associated with improved outcomes in patients with EGFR-mutant lung cancers with acquired resistance to EGFR TKI. Methods: Patients who received non–central nervous system local therapy were identified by a review of data from a prospective biopsy protocol for patients with EGFR-mutant lung cancers with acquired resistance to EGFR TKI therapy and other institutional biospecimen registry protocols. Results: Eighteen patients were identified, who received elective local therapy (surgical resection, radiofrequency ablation, or radiation). Local therapy was well tolerated, with 85% of patients restarting TKI therapy within 1 month of local therapy. The median time to progression after local therapy was 10 months (95% confidence interval [CI]: 2–27 months). The median time until a subsequent change in systemic therapy was 22 months (95% CI: 6–30 months). The median overall survival from local therapy was 41 months (95% CI: 26–not reached). Conclusions: EGFR-mutant lung cancers with acquired resistance to EGFR TKI therapy are amenable to local therapy to treat oligometastatic disease when used in conjunction with continued EGFR inhibition. Local therapy followed by continued treatment with an EGFR TKI is well tolerated and associated with long PFS and OS. Further study in selected individuals in the context of other systemic options is required.

Percutaneous computed tomography–guided radiofrequency ablation of renal masses in high surgical risk patients: preliminary results

This article evaluates the safety and efficacy of percutaneous radiofrequency ablation (RFA) delivered by computed tomography (CT) fluoroscopic guidance for the treatment of small, solitary renal lesions in high risk surgical and anesthetic patients. In total, 29 patients with 35 small (</=4 cm) renal lesions underwent a total of 37 CT fluoroscopically guided RFA treatments using a dry RFA technique. Because of medical comorbidities, 26 patients were considered high surgical risk candidates, and 3 patients had von Hippel-Lindau disease. Procedures were performed percutaneously, under intravenous sedation and on an outpatient basis. Renal lesions were monitored on a 3-month basis using precontrast- and postcontrast-enhanced CT imaging to assess for the presence of growth or residual lesion enhancement. Of 37 RFA treatments, 35 (95%) were successfully performed under intravenous sedation and 32 (86%) treatments were performed on an outpatient basis. Over a mean radiographic follow-up period of 9 months, 33 of 35 (94%) renal lesions have required only a single RFA treatment, and 2 patients required a second, successful retreatment for small regions of residual enhancement on follow-up CT imaging. Of 13 renal lesions with a >/=12-month radiographic follow-up interval, 11 (85%) have demonstrated no residual enhancement or growth after RFA. Percutaneous RFA of small, solitary renal lesions is well tolerated in high surgical risk patients. Although early results are encouraging, longer-term follow-up time is necessary to determine the precise role of RFA in this patient population. high resolution video, medium resolution video, low resolution video

Image-guided tumor ablation: standardization of terminology and reporting criteria--a 10-year update.

Image-guided tumor ablation has become a well-established hallmark of local cancer therapy. The breadth of options available in this growing field increases the need for standardization of terminology and reporting criteria to facilitate effective communication of ideas and appropriate comparison among treatments that use different technologies, such as chemical (eg, ethanol or acetic acid) ablation, thermal therapies (eg, radiofrequency, laser, microwave, focused ultrasound, and cryoablation) and newer ablative modalities such as irreversible electroporation. This updated consensus document provides a framework that will facilitate the clearest communication among investigators regarding ablative technologies. An appropriate vehicle is proposed for reporting the various aspects of image-guided ablation therapy including classification of therapies, procedure terms, descriptors of imaging guidance, and terminology for imaging and pathologic findings. Methods are addressed for standardizing reporting of technique, follow-up, complications, and clinical results. As noted in the original document from 2003, adherence to the recommendations will improve the precision of communications in this field, leading to more accurate comparison of technologies and results, and ultimately to improved patient outcomes.

Potent Induction of Tumor Immunity by Combining Tumor Cryoablation with Anti–CTLA-4 Therapy

Thermal ablation to destroy tumor tissue may help activate tumor-specific T cells by elevating the presentation of tumor antigens to the immune system. However, the antitumor activity of these T cells may be restrained by their expression of the inhibitory T-cell coreceptor CTLA-4, the target of the recently U.S. Food and Drug Administration-approved antibody drug ipilumimab. By relieving this restraint, CTLA-4-blocking antibodies such as ipilumimab can promote tumor rejection, but the full scope of their most suitable applications has yet to be fully determined. In this study, we offer a preclinical proof-of-concept in the TRAMP C2 mouse model of prostate cancer that CTLA-4 blockade cooperates with cryoablation of a primary tumor to prevent the outgrowth of secondary tumors seeded by challenge at a distant site. Although growth of secondary tumors was unaffected by cryoablation alone, the combination treatment was sufficient to slow growth or trigger rejection. In addition, secondary tumors were highly infiltrated by CD4(+) T cells and CD8(+) T cells, and there was a significant increase in the ratio of intratumoral T effector cells to CD4(+)FoxP3(+) T regulatory cells, compared with monotherapy. These findings documented for the first time an effect of this immunotherapeutic intervention on the intratumoral accumulation and systemic expansion of CD8(+) T cells specific for the TRAMP C2-specific antigen SPAS-1. Although cryoablation is currently used to treat a targeted tumor nodule, our results suggest that combination therapy with CTLA-4 blockade will augment antitumor immunity and rejection of tumor metastases in this setting.

Computerized Tomography Guided Percutaneous Renal Cryoablation With the Patient Under Conscious Sedation: Initial Clinical Experience

PURPOSE We report on our initial clinical experience with CT guided percutaneous renal cryoablation. MATERIALS AND METHODS CT guided percutaneous renal cryoablation was performed on 27 tumors using conscious sedation in 20 patients. Eligible patients had tumors of 5 cm or less and were poor surgical candidates or otherwise warranted nephron sparing treatment. Tumors were classified as central or noncentral depending on their relationship to the renal sinus fat. During cryoablation intraoperative active ice ball formation was monitored with real-time CT imaging to ensure adequate tumor coverage. Postoperative followup imaging was obtained at regular intervals. RESULTS Our method appears technically feasible as of the 27 cryoablations performed, only 1 complication occurred requiring blood transfusion in a patient with a large, centrally located tumor. To date we have 16 tumors in 12 patients with imaging followup of 1 month or more (mean followup 5.9 months). Mean baseline tumor size in this group was 2.5 cm with 11 small (3 cm or less) and 5 large (more than 3 cm) tumors. Of the tumors 5 were centrally located and 11 were noncentrally located. Preliminary data suggest that of the 16 cryoablated tumors 15 showed no signs of enhancement on followup. CONCLUSIONS CT guided percutaneous renal cryoablation appears to be a feasible treatment option for small, noncentrally located renal tumors. While early results appear promising, longer followup is needed to more clearly define the role of this treatment method.