Smoking linked to tumor heterogeneity for bladder Ca
August 18, 2017
Researchers from Wake Forest Baptist Comprehensive Cancer Center have made novel discoveries about the genomic signatures of cancers-including bladder cancer-in smokers and African-American patients.
Researchers from Wake Forest Baptist Comprehensive Cancer Center (WFBCC), Winston-Salem, NC have made novel discoveries about the genomic signatures of cancers-including bladder cancer-in smokers and persons of African-American ancestry.
The recently published findings (Theranostics 2017; 7:2914-23) provide strong evidence that tobacco is a major cause of genomic instability and heterogeneity in cancer, help to explain racial/ethnic disparities in cancer outcomes, and have implications for designing targeted therapy with existing and investigational agents, said senior author Wei Zhang, PhD, Wake Forest School of Medicine.
In the study, tumor samples were analyzed from 431 patients with advanced, treatment-refractory cancer who are enrolled in the Wake Forest Precision Oncology Trial. The genomic profiling was done by a commercial laboratory (Foundation Medicine) using Next Generation Sequencing and included analyses of mutations, rearrangement, and copy number alterations for 415 cancer-related genes.
Consistent with previous reports, the results showed a significantly higher mutational load in tumors of current smokers compared with those of former and never smokers and a high mutational load in smoking-related types of tumors. Using a new method for analyzing tumor clonality (SciClone), the investigators also identified increased intratumoral clonal heterogeneity in the smoking-related tumors; ie, the tumors were comprised of multiple “subtumors” having differing mutational landscapes.
Analyses with patients stratified by race/ethnicity showed that compared with Caucasian patients, the African-American patients had a similar mutational landscape overall. The African-Americans, however, had a significantly higher rate of mutations in two key genes-the tumor suppressor gene TP53 and KMT2C, a chromatin remodeling gene-along with significant amplification of five other oncogenes.
The findings for most of the gene mutations related to smoking and race/ethnicity were validated using data from patients enrolled in The Cancer Genome Atlas, Dr. Zhang told Urology Times.
“To our knowledge, we are the first to report that smoking is associated with tumor heterogeneity. This finding suggests that effective treatment for smoking-related tumors may require combination therapy with agents that are given together or sequentially to address multiple mutational targets,” said Dr. Zhang.
“The increased incidence of TP53 mutations in the African-Americans may help to explain racial disparities in response to chemotherapy and overall prognosis. Further study is needed, however, to understand the etiology for the observed difference in mutation pattern. The proportion of smokers was similar in the African-American and Caucasian subgroups in our cohort, and so smoking by itself is not the explanation. In the absence of more granular information on smoking habits, we cannot rule out differences in what is being smoked and how much. Differences in diet and/or genetic predisposition may also be involved and are issues that we plan to explore in follow-up studies.”
Dr. Zhang noted that compared with most other major cancer centers in the United States, WFBCC has a unique opportunity to interrogate mutational events linked to smoking and African-American ancestry because its catchment area includes high proportions of patients with these characteristics. Among the 431 patients included in the study, 127 (29.5%) were current smokers (29.5%), 145 (33.6%) were former smokers (33.6%), 162 had (37.6%) common smoking-related cancer types (eg, lung, colorectal, bladder), and 58 (13.5%) were African-Americans.
In the Wake Forest Precision Oncology Trial, oncologists at WFBCC are using information from the mutational analyses to identify actionable targets and design treatment regimens. So far, there have been some very encouraging responses. Dr. Zhang described a case involving a patient diagnosed with stage II invasive high-grade urothelial carcinoma of the bladder as an example.
The patient developed lung metastases 4 months after cystoprostatectomy and then received six cycles of carboplatin/gemcitabine followed by 14 cycles of paclitaxel (Abraxane). After 20 months, his treatment was changed to pazopanib (Votrient), an FGFR inhibitor, after genomic profiling of a biopsy sample from a growing lung nodule identified an FGFR3 activating mutation.
“Serial follow-up imaging after the switch to pazopanib showed progressive decrease in the size of his lung nodules,” Dr. Zhang said.
Foundation Medicine is covering the cost of the mutational analyses for the first 2 years of the Precision Oncology Trial.
“Next Generation Sequencing is expensive, but the cost is already coming down and should continue to decrease. Then the precision medicine approach may be extended to cancer patients at an earlier stage in their disease,” Dr. Zhang said.