ESMO @ ECC 2013: Targeted Treatment Options May Arise from Molecular Profiling of Patients with Cancers of Unknown Primary Site

Paradigm shift in CUP treatment approach

Pathway analysis and identification of the oncogenic drivers of these pathways can provide information on druggable targets, even for cancers of unknown primary site (CUP), and may open the door to new treatment options for patients with CUP. Dr Zoran Gatalica presented late breaking findings on 30 September during the Drug Development Proffered Papers Session (Abstract E17-7084) at the 17th ECCO – 38th ESMO – 32nd ESTRO European Cancer Congress. The European Cancer Congresses are organised in joint partnership with ESSO, EACR, EONS and SIOPE as a forum for the latest in oncology research and to offer multidisciplinary and multi-professional educational opportunities in oncology. The 2013 Congress convened in Amsterdam, The Netherlands from 27 September until 01 October.

Pitfalls in traditional treatment classification of CUP

An estimated 3 to 5% of cancers are CUP, which associates with a poorer prognosis. The quest to identify the primary origin in CUP has been led by testing for biomarker expression indicative of a potential site of origin, in order to tailor the therapy based on the presumption of the primary tumour type. However, this approach is often limited by providing just the statistical odds of one site being correct over another and, for the most part, does not provide information on actionable biomarkers.

Recent identification of actionable molecules occurring in common oncogenic pathways has provided druggable targets that are independent of the primary cancer site and may avail CUP patients to new treatment options.

Pathway-driven treatment opportunities

Dr. Zoran Gatalica of the Department of Oncologic Pathology headed a team of investigators from Caris Life Sciences, Phoenix, USA and Basel, Switzerland that sought to change the treatment focus from detecting the origin of CUP to identifying the relevant pathways and targetable molecules within them. The team analysed data from a large scale profiling of 1350 patients with CUP from a referral laboratory at Caris Life Sciences, Phoenix, USA to obtain information on biomarkers associated with the potential for drug response.

Biomarker expression was determined using mutational  analyses, including next generation sequencing, Sanger pyrosequencing, quantitative polymerase chain reaction (qPCR) and restriction fragment length polymorphism (RFLP), in-situ hybridisation by fluorescent and chromogenic methods, immunohistochemistry, reverse transcriptase (RT)-qPCR and fragment analysis.

Actionable biomarkers were identified in 77% of cases and included targetable protein overexpression, such as steroid receptors and  MET, protein loss as seen with PTEN loss of expression, activating mutations that included  EGFR, BRAF, PIK3CA and gene copy number variations, such as HER2, TOP2A and MET gene amplification.

The analysis also identified disease-defining gene mutations, such as somatic GNA11 mutation, that resulted in the disease being re-classified from metastatic melanoma of unknown primary to primary leptomeningeal melanocytoma.

Pathway analysis and identification of druggable targets were concluded to be applicable to patients with CUP because this method identifies treatment options not traditionally considered for most CUP. The authors cited the example of a recently published case study where  an EGFR inhibitor (gefitinib) was successfully implemented in a patient with CUP based on the detection of an activating mutation (L858R) that resulted in a remarkable and durable response (JCO 2013;31:e237).

The authors reported the following conflict of interest: Employment by and ownership of Caris Life Sciences stock options.