October 2015, Vol. 4, No. 5
Identifying Targets in Anal Squamous Cell Carcinoma:
An Interview with Patrick Boland, MD, of Roswell Park Cancer Institute
At the recent ASCO Annual Meeting, Patrick Boland, MD, of Roswell Park Cancer Institute, submitted an abstract entitled Comprehensive Multiplatform Biomarker Analysis of 212 Anal Squamous Cell Carcinomas highlighting the need to identify novel potential targets and therapeutic options for less common malignancies. In his study, investigators analyzed 212 anal squamous cell carcinomas using a multiplatform tumor profiling approach to identify potential therapeutic targets for this rare malignancy, in particular for those cases of recurrence and metastases for which few therapeutic options exist. The results of this analysis allowed researchers to identify potential treatment options not routinely considered, such as the therapies that target the PI3 kinase pathway, epidermal growth factor receptor (EGFR) inhibitors, or newer-generation pan-HER inhibitors.
The publishers of PMO had the opportunity to speak with Dr Boland about this study.
PMO Can you discuss the current treatment options for patients who present with recurrent or metastasized squamous cell anal carcinoma?
Dr Boland Although research advances have enhanced our understanding of rare and aggressive cancer subtypes, patients living with these malignancies have few therapeutic options. When patients are diagnosed, they are treated according to the advanced state or stage of disease. In local and locally advanced anal carcinoma (AC), concomitant chemoradiation therapy based on mitomycin C and 5-fluorouracil (5-FU) is currently the optimal treatment, while for patients with metastatic AC, chemotherapy with 5-FU and cisplatin remains the gold standard. There are no indications for induction or maintenance therapies in locally advanced tumors. Many novel strategies, such as targeted therapies, vaccination, immunotherapy, and photodynamic therapy, are in clinical trials for the treatment of AC, with many of us hoping we might see significant benefits from these new approaches.
PMO Please explain the state of biomarker identification in this population of gastrointestinal cancer patients.
Dr Boland Although there have been great strides made in identifying biomarkers using multiplatform molecular tumor profiling, at this point, there are no clear biomarkers to guide treatment for anal cancer. While most anal cancers (85%-90%) are thought to be related to human papillomavirus (HPV), those anal cancers that are HPV negative more commonly possess p53 mutations. Recent data suggest that these HPV-negative tumors are less responsive to standard treatments and as a result have a worse prognosis. There have been a few series published examining biomarkers or mutations in anal cancers, but all involving only a small number of patients or examining only a few biomarkers.
PMO Are tumors from patients with this disease routinely analyzed for biomarkers and/or genetic mutations?
Dr Boland Typically, when a patient is diagnosed, treatment is restricted to the traditional methods previously described. Our goal is to demonstrate that routine analysis of biomarkers can help us to understand more about recurrent or metastasized squamous cell anal carcinoma and ultimately allow us to target treatment accordingly.
PMO Can you describe the multiplatform analysis you employed in evaluating the tumor specimens?
Dr Boland The 212 squamous cell anal carcinoma specimens were tested using Caris Molecular Intelligence, a multiplatform tumor profiling service consisting of gene sequencing (Sanger or next-generation sequencing), protein expression (immunohistochemistry), and gene amplification (chromogenic in situ hybridization or fluorescence in situ hybridization). This provides us with a more complete picture of the disease, possibly allowing us to make more informed treatment decisions.
PMO What biomarkers emerged as possible targets for novel therapies?
Dr Boland The ability to interrogate a tumor’s molecular composition using tumor profiling technologies has enabled us to identify a steady stream of gene mutations, which help guide the treatment decision process. Specifically, what we have learned from this study is that mutations in PIK3CA, AKT1, and FBXW7, along with PTEN loss, indicate a potential for targeting the PI3 kinase pathway in patients with anal squamous cell carcinoma. Preliminary data presented at ASCO demonstrated benefit of CHK1/2 inhibitors in anal squamous cell cancers, with an early signal suggesting preferential benefit in tumors with PI3K pathway alterations. Targeting the ErbB-family receptors, namely with anti-EGFR agents or newer-generation pan-HER inhibitors, may represent another option, given EGFR and HER2 amplification as well as EGFR overexpression. Finally, differences in anal carcinomas whose etiology is of viral origin may present different treatment options based on the driver mutations. All of these molecular characteristics represent intriguing areas for future research.
PMO Are there considerations for those patients whose disease is viral—HIV or HPV—in origin?
Dr Boland For head and neck squamous cell cancers (HNSCCs), we see marked differences between the molecular profile of HPV-negative and HPV-positive tumors, with increased PI3K alterations in the HPV-positive subset and increased incidence of p53 mutations and growth factor receptor amplifications (EGFR, HER2) in the HPV-negative subset. HPV-related anal carcinomas are likely to differ markedly from non–HPV-related tumors with respect to driver mutations and alterations. Unfortunately, it is not conclusive at this point whether the alterations mirror those seen in HNSCC or are different altogether. At present, based on HPV status alone, immunotherapy trials that target HPV-transformed cells represent an appealing option.
PMO What are the next steps in broadening the treatment options for these patients?
Dr Boland All of these molecular characteristics, which have been discovered using multiplatform molecular profiling technologies, represent intriguing areas for future research. Ultimately, through the identification of possible targets for therapy, we hope that patients will be able to access personalized treatments based on their cancer’s specific molecular alterations. Further examination of these data sets will hopefully allow for trials that can select or stratify patients based on their molecular profile.
PMO Thank you very much for your time today, we wish you continued success in your research endeavors.
Dr Boland Thank you, it was my pleasure.
Despite the promise of molecular profiling, approximately 80% of patients with lung cancer lack a defined genotypic mutation and thus become resistant when treated with a tyrosine kinase inhibitor. According to data presented at the congress, however, lung cancer remains a highly mutated disease, suggesting great potential for immunotherapy. “If [ Read More ]
Genetic testing in metastatic melanoma should include testing for all actionable mutations in exon 15, said Grant McArthur, MB, BS, PhD, at the 2015 World Cutaneous Malignancies Congress. Testing at the time of disease progression is not yet ready for routine clinical use. Test the Metastases In metastatic melanoma, tumor [ Read More ]