Targeted Therapy for Cancer in the Genomic Era
2015; 21 (4): 294-298
Chromosomal copy number alterations for associations of ductal carcinoma in situ with invasive breast cancer.
Breast cancer research
2015; 17: 108-?
The advent of cancer genomics has led to the development of many highly successful targeted therapies, primarily inhibitors of growth factor receptors and related kinases, including imatinib for chronic myeloid leukemia and trastuzumab for HER2-positive breast cancer. This approach has become highly successful for certain cancers. However, as the list of targeted therapies expands, their efficacy becomes more limited, and toxicity accumulates. What we have learned in the past decades is that while the targeted therapeutics approach may be highly successful in less complex tumors, cancers defined by carcinogen-induced genomic chaos, such a UV-induced melanoma or tobacco-induced lung cancer, are driven by a multitude of competing molecular pathways and, as such, are not as successfully managed by a similar approach. Luckily, in the past years, the field of cancer immunotherapy has become more fully developed with the emergence of checkpoint blockade inhibitor therapy. These promising new agents are particularly well suited for tumors with a high mutational burden due to underlying genomic disarray. While still in its infancy, we predict that cancer immunotherapy will offer a better alternative to our current targeted approach and eagerly await the results of several ongoing clinical trials that will elucidate this new direction in cancer therapy.
View details for DOI 10.1097/PPO.0000000000000135
View details for Web of Science ID 000359820200010
View details for PubMedID 26222081
Lenalidomide, melphalan and dexamethasone in a population of patients with immunoglobulin light chain amyloidosis with high rates of advanced cardiac involvement
2013; 98 (10): 1593-1599
Screening mammography has contributed to a significant increase in the diagnosis of ductal carcinoma in situ (DCIS), raising concerns about overdiagnosis and overtreatment. Building on prior observations from lineage evolution analysis, we examined whether measuring genomic features of DCIS would predict association with invasive breast carcinoma (IBC). The long-term goal is to enhance standard clinicopathologic measures of low- versus high-risk DCIS and to enable risk-appropriate treatment.We studied three common chromosomal copy number alterations (CNA) in IBC and designed fluorescence in situ hybridization-based assay to measure copy number at these loci in DCIS samples. Clinicopathologic data were extracted from the electronic medical records of Stanford Cancer Institute and linked to demographic data from the population-based California Cancer Registry; results were integrated with data from tissue microarrays of specimens containing DCIS that did not develop IBC versus DCIS with concurrent IBC. Multivariable logistic regression analysis was performed to describe associations of CNAs with these two groups of DCIS.We examined 271 patients with DCIS (120 that did not develop IBC and 151 with concurrent IBC) for the presence of 1q, 8q24 and 11q13 copy number gains. Compared to DCIS-only patients, patients with concurrent IBC had higher frequencies of CNAs in their DCIS samples. On multivariable analysis with conventional clinicopathologic features, the copy number gains were significantly associated with concurrent IBC. The state of two of the three copy number gains in DCIS was associated with a risk of IBC that was 9.07 times that of no copy number gains, and the presence of gains at all three genomic loci in DCIS was associated with a more than 17-fold risk (P = 0.0013).CNAs have the potential to improve the identification of high-risk DCIS, defined by presence of concurrent IBC. Expanding and validating this approach in both additional cross-sectional and longitudinal cohorts may enable improved risk stratification and risk-appropriate treatment in DCIS.
View details for DOI 10.1186/s13058-015-0623-y
View details for PubMedID 26265211
More Than a Frog in the Throat A Case Series and Review of Localized Laryngeal Amyloidosis
ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY
2012; 138 (5): 509-511
Immunoglobulin light chain amyloidosis remains incurable despite recent therapeutic advances, and is particularly difficult to treat in patients with amyloid cardiomyopathy. Based on evidence of activity in multiple myeloma, we designed a pilot study of an oral regimen of lenalidomide in combination with dexamethasone and low dose melphalan in order to evaluate its safety and efficacy in patients with amyloidosis, including those with advanced cardiac involvement. Twenty-five patients were enrolled. Ninety-two percent of patients had cardiac involvement by amyloidosis, and 36% of patients met criteria for Mayo Clinic cardiac stage III disease. Patients received up to 9 cycles of treatment, consisting of lenalidomide 10 mg/day orally on days 1 - 21 (28 day cycle); melphalan 0.18mg/kg orally on days 1-4; and dexamethasone 40 mg orally on days 1, 8, 15, 22. High rates (33%) of cardiac arrhythmias and low rates of treatment completion (12.5%) were observed. Ten patients died during the study, all within the first several months of treatment due to acute cardiac events. The overall hematologic response rate was 58%, however organ responses were seen in only 8% of patients. Overall survival at one year was 58%. While we confirmed the hematologic response rates observed with similar regimens, front line treatment with melphalan, lenalidomide and dexamethasone was toxic, ineffective, and did not alter survival outcomes for patients with high risk cardiac disease. Our data highlight the importance of developing novel treatment approaches for amyloid cardiomyopathy. The trial was registered at www.clinicaltrials.gov (NCT00890552).
View details for DOI 10.3324/haematol.2013.084574
View details for Web of Science ID 000328543400020
View details for PubMedID 23716538