There have been a significant number of advances in bladder cancer genomics in the past few years, and with increased collaboration and development of new techniques, we are working to unlocking the inner mechanics of bladder cancer and upper tract urothelial carcinoma (UTUC).
In today’s session, the four abstracts helped address the incidence and impact of germline mutations and somatic mutations on urothelial cancer. As he reviewed, genetic mutations, in and of themselves, carry little clinical implication. They are merely the first step in a biologic cascade that leads to a specific phenotype – disease development, drug resistance, metastatic spread, etc. Germline and somatic mutations vary significantly: germline mutations are heritable, constitutional, and are determined by comparison to only a reference genome, whereas, somatic mutations are non-heritable, sometimes clonal, and have to be compared to both a reference sequence and account for germline mutations. As the germline needs to be better preserved from an evolutionary standpoint, the difference in the number of somatic and germline mutations is often on the order of 100X.
DNA damage repair (DDR) genes are critically important in preserving genomic integrity – and disruption in any of their pathways can lead to clinical development of malignancy, as in the case of Lynch syndrome, which is a well-known heritable genetic mutation in a DDR pathway. Indeed, Lynch syndrome and its association with urothelial carcinoma (specifically upper tract UC) has long been known – the Amsterdam II criteria include UTUC in familial relations.
Based on this, he aimed to address three main topics.
1) What is the relationship between germline mutations and urothelial carcinoma?
Work by MSKCC (presented by Dr. Carlo) and Dr. Faltas both demonstrated higher than expected rates of germline mutations (22-48%) in their UC cohorts. Based on this and the above knowledge of Lynch syndrome and UTUC, he recommends genetic testing for germline mutations in patients with UTUC. In bladder UC though, while he feels this may be a future standard, at this time, it should be in context of a research protocol, and positive findings should trigger referral to a genetic counselor.
Since germline mutations can be mosaic in nature, further understanding of the pathogenic nature of the mutations must be clarified prior to clinical decision making based on the results of these tests.
2) Can somatic mutations predict response to immunotherapy in UC?
Prior work has demonstrated that mutational load correlates with immunotherapy response, with higher mutational load more likely to lead to complete or partial response (CR/PR). Mutational load also correlated to neoantigen load in UC, which may account for the clinical response.
Two of the abstracts today (Dr. Teo and Dr. Iyer from MSKCC) demonstrated that somatic DDR mutations and mismatch repair gene defects can correlate with immune checkpoint blockade clinical efficacy. Indeed, the approval of pembrolizumab for any metastatic or unresectable solid tumor with high microsatellite instability (MSI-H) or mismatch repair deficiency (MMR-D) is evidence of this.
3) Does tumor heterogeneity shape response to systemic therapy?
Prior work by Dr. Faltas and colleagues demonstrated that many mutations are “private” in patients with UC, even in a single patient at different time points in treatment. Neoantigens can also arise independently – indeed, only 7% of neoepitodes were shared among UC metastases. This heterogeneity may contribute to the non-response rate or failure rate in certain patients. As was discussed by Dr. Liu from Dana Farber Cancer Institute (Abstract 4511), a greater number of subclonal mutations is associated with worse overall survival in patients with UC treated with neoadjuvant chemotherapy and radical cystectomy. The same likely applies to ICB response.
Dr. Faltas’ prior work on genomic heterogeneity in multiple UC tissues from a single patient over course of treatment demonstrated that even the primary tumor was a downstream branch from an earlier ancestor clone. As such, treatment based on the genomic make-up of the primary tumor or any individual metastases would likely miss significant genomic changes present in other tissue in the body.
In conclusion, UC genomics continues to rapidly evolve. As our understanding of UC biology grows, the subsequent changes have the potential to significantly impact clinical care. Take-home points are that:
1) Germline mutations are more common than previously known. Family history and screening are critically important and germline testing should be considered.
2) Somatic DDR mutations are associated with better outcomes with immunotherapy. Better tests may help better select patients for systemic therapy or immunotherapy.
3) UC tumor heterogeneity and evolution are major barriers to durable clinical responses.
Presented By: Bishoy Faltas, MD, Weill Cornell Medical College
Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto
1. Faltas BM, et al. Clonal evolution of chemotherapy-resistant urothelial carcinoma. Nat Genet. 2016 Dec;48(12):1490-1499. doi: 10.1038/ng.3692. Epub 2016 Oct 17.
2. Hafner C, Toll A, Real FX. HRAS mutation mosaicism causing urothelial cancer and epidermal nevus. N Engl J Med. 2011 Nov 17;365(20):1940-2. doi: 10.1056/NEJMc1109381.
3. Milholland B, Dong X, Zhang L, Hao X, Suh Y, Vijg J. Differences between germline and somatic mutation rates in humans and mice. Nat Commun. 2017 May 9;8:15183. doi: 10.1038/ncomms15183.
at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA