Genomic Profiling of Cancer of Unknown Primary Site
Identification of novel treatment relevant paradigms to address the limited options and poor prognosis of patients with CUP
Genomic profiling of cancer of an unknown primary site (CUP) found at least one clinically relevant genomic alteration in most of the samples tested, an indication of potential to influence and personalise therapy for this type of cancer, which responds poorly to classical chemotherapy, according to a study published online on February 12 by JAMA Oncology.
Between 2% and 9% of all cancer diagnoses present as a metastatic CUP, and about two-thirds of CUP tumours are adenocarcinomas. No drugs are specifically approved to treat CUP and because the response to non-targeted chemotherapy treatments is poor, 5-year survival is currently about 11% and median overall survival ranges from 11 weeks to 11 months, according to the study background.
Dr Jeffrey Ross of Foundation Medicine, Inc., and Albany Medical College, USA and co-authors performed genomic profiling on 200 CUP samples to look for targetable genomic alterations that might identify opportunities to targeted therapies for patients with CUP. Of the 200 samples, 125 were adenocarcinomas of unknown primary site and 75 other CUPs without the features of adenocarcinomas.
The authors identified at least one genomic alteration in 192 (96%) of CUP specimens. Within the 200 samples, a total of 841 alterations were identified in 121 genes, for an average of 4.2 genomic alterations per tumour. One or more potentially targetable genomic alterations also was identified in 169 of 200 (85%) CUP specimens.
The most frequent genomic alterations were in TP53 (55%), KRAS (20%), CDKN2A (19%), MYC (12%), ARID1A (11%), MCL1 (10%), PIK3CA (9%), ERBB2 (8%), PTEN (7%), EGFR (6%), SMAD4 (7%), STK11 (7%), SMARCA4 (6%), RB1 (6%), RICTOR (6%), MLL2 (6%), BRAF (6%), and BRCA2 (6%).
Mutations or amplifications of ERBB2 were more frequent in adenocarcinoma (10%) than in non-adenocarcinoma CUPs (4%). Alterations of EGFR (8% vs. 3%) and BRAF (6% vs. 4%) were more common in adenocarcinoma than in non-adenocarcinoma CUPs.
Clinically relevant alterations were more frequent in the receptor tyrosine kinase/Ras/mitogen-activated protein kinase signalling pathway. The alterations like ALK, ARAF, BRAF, EGFR, FGFR1, FGFR2, KIT, KRAS, MAP2K1, MET, NF1, NF2, NRAS, RAF1, RET, and ROS1 were found in 72% adenocarcinoma of unknown primary site but in only 39% non-adenocarcinoma CUPs (p <0.001).
The authors highlight a number of important limitations to this work and note that prospective randomised clinical trials are needed to confirm the observations described in the present study.
"Given the poor prognosis of CUP treated by nontargeted conventional therapies, comprehensive genomic profiling shows promise to identify targeted therapeutic approaches to improve outcomes for this disease while potentially reducing the often costly and time-consuming search for the tumor's anatomic site of origin," the study concludes.
At the time of manuscript submission, all authors were employees and equity holders of Foundation Medicine, Inc.
CUP: The poster child for personalised medicine?
In an accompanied editorial article, Dr Gauri Varadhachary of the University of Texas MD Anderson Cancer Center, Houston, USA writes: "From a development perspective, it is especially encouraging that several molecular targets may be independent of the tumor site, making it possible to include patients with CUP in new studies of targeted therapies and allowing us to piggyback on the broader advances in personalized cancer therapy. We will require creative approaches to clinical studies and learning from the current trends. These trends can then perhaps help in establishment of an international CUP mutation consortium that groups CUP subtypes (e.g., liver, osseous, nodal, carcinomatosis dominant presentations) and mutations to plan innovative smaller trials. Just as we need to be selective in our diagnostic approach using an effective algorithm that leverages the proteomics and genomics techniques, we need to be selective in our research efforts to deliver validated new approaches to our patients with CUP."
Ross JS, Wang K, Gay L,et al.Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Site. New Routes to Targeted Therapies.JAMA Oncol 2015; Published online February 12. doi:10.1001/jamaoncol.2014.216