Bishoy Faltas

Whole-Exome Sequencing of Metastatic Cancer and Biomarkers of Treatment Response

IMPORTANCE Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low-frequency mutations. We describe a whole-exome sequencing (WES) precision medicine trial focused on patients with advanced cancer. OBJECTIVE To understand how WES data affect therapeutic decision making in patients with advanced cancer and to identify novel biomarkers of response. DESIGN, SETTING, AND PATIENTS Patients with metastatic and treatment-resistant cancer were prospectively enrolled at a single academic center for paired metastatic tumor and normal tissue WES during a 19-month period (February 2013 through September 2014). A comprehensive computational pipeline was used to detect point mutations, indels, and copy number alterations. Mutations were categorized as category 1, 2, or 3 on the basis of actionability; clinical reports were generated and discussed in precision tumor board. Patients were observed for 7 to 25 months for correlation of molecular information with clinical response. MAIN OUTCOMES AND MEASURES Feasibility, use of WES for decision making, and identification of novel biomarkers. RESULTS A total of 154 tumor-normal pairs from 97 patients with a range of metastatic cancers were sequenced, with a mean coverage of 95X and 16 somatic alterations detected per patient. In total, 16 mutations were category 1 (targeted therapy available), 98 were category 2 (biologically relevant), and 1474 were category 3 (unknown significance). Overall, WES provided informative results in 91 cases (94%), including alterations for which there is an approved drug, there are therapies in clinical or preclinical development, or they are considered drivers and potentially actionable (category 1-2); however, treatment was guided in only 5 patients (5%) on the basis of these recommendations because of access to clinical trials and/or off-label use of drugs. Among unexpected findings, a patient with prostate cancer with exceptional response to treatment was identified who harbored a somatic hemizygous deletion of the DNA repair gene FANCA and putative partial loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response. CONCLUSIONS AND RELEVANCE The majority of advanced, treatment-resistant tumors across tumor types harbor biologically informative alterations. The establishment of a clinical trial for WES of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response.

Clonal evolution of chemotherapy-resistant urothelial carcinoma

Chemotherapy-resistant urothelial carcinoma has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs the evolution of urothelial carcinoma and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 urothelial carcinoma samples, including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights: (i) chemotherapy-treated urothelial carcinoma is characterized by intra-patient mutational heterogeneity, and the majority of mutations are not shared; (ii) both branching evolution and metastatic spread are very early events in the natural history of urothelial carcinoma; (iii) chemotherapy-treated urothelial carcinoma is enriched with clonal mutations involving L1 cell adhesion molecule (L1CAM) and integrin signaling pathways; and (iv) APOBEC-induced mutagenesis is clonally enriched in chemotherapy-treated urothelial carcinoma and continues to shape the evolution of urothelial carcinoma throughout its lifetime.

Recurrence Patterns After Open and Robot-assisted Radical Cystectomy for Bladder Cancer

BACKGROUND Concerns remain whether robot-assisted radical cystectomy (RARC) compromises survival because of inadequate oncologic resection or alteration of recurrence patterns. OBJECTIVE To describe recurrence patterns following open radical cystectomy (ORC) and RARC. DESIGN, SETTING, AND PARTICIPANTS Retrospective review of 383 consecutive patients who underwent ORC (n=120) or RARC (n=263) at an academic institution from July 2001 to February 2014. INTERVENTION ORC and RARC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Recurrence-free survival estimates were illustrated using the Kaplan-Meier method. Recurrence patterns (local vs distant and anatomic locations) within 2 yr of surgery were tabulated. Cox regression models were built to evaluate the effect of surgical technique on the risk of recurrence. RESULTS AND LIMITATIONS The median follow-up time for patients without recurrence was 30 mo (interquartile range [IQR] 5-72) for ORC and 23 mo (IQR 9-48) for RARC (p=0.6). Within 2 yr of surgery, there was no large difference in the number of local recurrences between ORC and RARC patients (15/65 [23%] vs 24/136 [18%]), and the distribution of local recurrences was similar between the two groups. Similarly, the number of distant recurrences did not differ between the groups (26/73 [36%] vs 43/147 [29%]). However, there were distinct patterns of distant recurrence. Extrapelvic lymph node locations were more frequent for RARC than ORC (10/43 [23%] vs 4/26 [15%]). Furthermore, peritoneal carcinomatosis was found in 9/43 (21%) RARC patients compared to 2/26 (8%) ORC patients. In multivariable analyses, RARC was not a predictor of recurrence. Limitations of the study include selection bias and a limited sample size. CONCLUSIONS Within limitations, we found that RARC is not an independent predictor of recurrence after surgery. Interestingly, extrapelvic lymph node locations and peritoneal carcinomatosis were more frequent in RARC than in ORC patients. Further validation is warranted to better understand the oncologic implications of RARC. PATIENT SUMMARY In this study, the locations of bladder cancer recurrences following conventional and robotic techniques for removal of the bladder are described. Although the numbers are small, the results show that the distribution of distant recurrences differs between the two techniques.

Cornering metastases: therapeutic targeting of circulating tumor cells and stem cells

The last decade has witnessed an evolution of our understanding of the biology of the metastatic cascade. Recent insights into the metastatic process show that it is complex, dynamic, and multi-directional. This process starts at a very early stage in the natural history of solid tumor growth leading to early development of metastases that grow in parallel with the primary tumor. The role of stem cells in perpetuating cancer metastases is increasingly becoming more evident. At the same time, there is a growing recognition of the crucial role circulating tumor cells (CTCs) play in the development of metastases. These insights have laid the biological foundations for therapeutic targeting of CTCs, a promising area of research that aims to reduce cancer morbidity and mortality by preventing the development of metastases at a very early stage. The hematogenous transport phase of the metastatic cascade provides critical access to CTCs for therapeutic targeting aiming to interrupt the metastatic process. Recent advances in the fields of nanotechnology and microfluidics have led to the development of several devices for in vivo targeting of CTC during transit in the circulation. Selectin-coated tubes that target cell adhesion molecules, immuno-magnetic separators, and in vivo photo-acoustic flow cytometers are currently being developed for this purpose. On the pharmacological front, several pharmacological and immunological agents targeting cancer stem cells are currently being developed. Such agents may ultimately prove to be effective against circulating tumor stem cells (CTSCs). Although still in its infancy, therapeutic targeting of CTCs and CTSCs offers an unprecedented opportunity to prevent the development of metastasis and potentially alter the natural history of cancer. By rendering cancer a “local” disease, these approaches could lead to major reductions in metastasis-related morbidity and mortality.

Identifying Circulating Tumor Stem Cells That Matter: The Key to Prognostication and Therapeutic Targeting

TO THEEDITOR: We read with interest the article by Iinuma et al 1 that describes their study examining the clinical significance of cancer stem cells in the peripheral blood of patients with colorectal cancer (CRC). The defining characteristics of a circulating cancer stem cell (CTSC) are its capacity for self-renewal and for initiation of distant metastases; some of these cells are also resistant to traditional chemo- therapy. 2,3 The concept that circulating tumor stem cells can be iden- tified and targeted is attractive and has major diagnostic, prognostic, and therapeutic implications for patients with metastatic cancer. However, the identification of authentic CTSCs continues to be a challenge because of the lack of a clear understanding of the biologic heterogeneity of tumor stem-cell populations and also because of the lack of characterization of surface markers that predict clinically im- portant subsets of CTSCs, such as those with aggressive malignant potential or drug resistance.

Myelodysplastic syndromes: toward a risk-adapted treatment approach

Several classification and scoring systems have been developed in myelodysplastic syndromes (MDS to predict the risk of progression to acute myeloid leukemia and survival. These prognostication models have been also used to inform therapeutic decision-making in a risk-adapted fashion. Patient-related factors such as age, comorbidities, and functional status have to be considered as well. Here we review a risk-guided therapeutic approach for the management of MDS patients. It is anticipated that the improved understanding of the complex pathogenesis of MDS and the recent discovery of important molecular lesions will be translated into novel therapeutic approaches. Additionally, some prognostic aberrations are expected to be incorporated into the prognostic tools with the goal of improving their prognostic precision and therefore allow for a more informed therapeutic decision-making based on the individual’s risk profile.

Sacituzumab Govitecan, a Novel Antibody–Drug Conjugate, in Patients With Metastatic Platinum-Resistant Urothelial Carcinoma

Patients with metastatic, platinum-resistant urothelial carcinoma (PRUC) have no Food and Drug Administration-approved therapies. The response rates to second-line chemotherapy have generally been < 20%, with a median overall survival of < 1 year. We report our experience with 6 heavily pretreated patients with advanced PRUC (ClinicalTrials.gov identifier NCT01631552) with the novel antibody-drug conjugate, sacituzumab govitecan (IMMU-132). This antibody-drug conjugate comprises the active metabolite of irinotecan, SN-38, conjugated to an anti-Trop-2 antibody. Trop-2 is widely expressed in ≤ 83% of urothelial carcinomas. Of the 6 patients, 3 had a clinically significant response (progression-free survival, 6.7 to 8.2 months; overall survival, 7.5+ to 11.4+ months). Sacituzumab govitecan was well tolerated. Because of these results, a phase II trial has been initiated. The present report highlights the promise of antibody-drug conjugates, such as sacituzumab govitecan, as a novel therapeutic strategy for the treatment of PRUC.

Myelodysplastic syndromes: What do hospitalists need to know?

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem cell disorders characterized by dysplasia, ineffective hematopoiesis leading to peripheral blood cytopenias, and a variable risk of leukemic progression. MDS primarily affects the elderly, and although its prevalence is increasing, MDS is frequently overlooked and underdiagnosed. MDS should be suspected in any patient with unexplained cytopenias, and a bone marrow evaluation is ultimately needed to make the diagnosis and exclude other causes of bone marrow failure. The last 15 years have witnessed significant advances in our understanding of the complex pathogenesis, classification and prognostication, and therapeutic approaches to MDS. Several prognostic models facilitate outcome prediction and risk-adapted therapy. The addition of azacitidine, decitabine, and lenalidomide to erythropoiesis-stimulating agents in our armamentarium offered new effective therapeutic options for many patients who are not candidates for intensive interventions. Improved understanding of the genetic, epigenetic, and immunologic mechanisms that operate in MDS will help develop better prognostication tools and rationally design more effective therapies. Hospitalists are likely to encounter both patients with MDS and patients in whom MDS should be suspected. In this review of MDS, we focus on the epidemiology, diagnosis, pathogenesis, classification and prognostic tools, and treatment options.

Blocking immune checkpoints in prostate, kidney, and urothelial cancer: An overview

Despite a long history of immunotherapeutic approaches to treatment, most genitourinary malignancies are not cured by existing immunotherapy regimens. More recently, cell surface molecules known as immune checkpoints have become the focus of efforts to develop more effective immunotherapies. Interactions between these molecules and their ligands inhibit the proliferation and function of tumor-specific lymphocytes. A monoclonal antibody blocking 1 of these checkpoints was approved for the treatment of metastatic melanoma and is now being tested in other malignancies. The objective responses seen in these early trials of checkpoint blockade are driving renewed enthusiasm for cancer immunotherapy. There are several ongoing and planned trials in genitourinary malignancies of single-agent inhibitors, as well as combinations targeting multiple checkpoints or adding other types of therapies to checkpoint blockade.

Immunologics and Chemotherapeutics for Renal Cell Carcinoma

Treatment of metastatic renal cell carcinoma remains a challenge for clinicians. Traditional chemotherapy is ineffective and immunotherapy with interleukin-2 is only occasionally beneficial. The development of numerous agents targeting vascular endothelial growth factor and mammalian target of rapamycin signaling pathways that have been studied in phase III trials have resulted in significant improvement in survival for patients with clear cell renal cell carcinoma. Currently available U.S. Food and Drug Administration-approved first line targeted agents include sunitinib, pazopanib, temsirolimus, and bevacizumab (with interferon), while axitinib, everolimus, and sorafenib are most extensively used following progression as second- or third line therapy. Attempts to augment the activity of these agents by combining them together or with chemotherapy or immunotherapy have not yet proven to improve outcomes. As a result, the sequential use of single agents remains the current standard of care.