DNA profiling is revealing novel treatment choices for patients with cancer whose disease has spread by the time they are diagnosed and no primary tumour site of origin can be found – so-called carcinoma of unknown primary (CUP).

Research reported at the ESMO Congress 2019 showed that approximately one in three patients with CUP may not be adequately treated with standard chemotherapy but may be suitable for matched targeted treatment or immunotherapy based on DNA changes in their tumour. 

“Standard treatment for CUP has not changed in decades so, if we can change the outcome for the one in three patients with targetable mutations identified by DNA profiling, that could have an important impact on CUP therapy,” said Prof Jeffrey Ross, Upstate Medical University, Syracuse, USA, first author of one of the reported studies.

CUP affects approximately one in 15 patients with cancer, despite investigations to try to identify the primary tumour from which the cancer has spread. 

They then receive anti-cancer treatment and/or palliative care to relieve symptoms arising from the spread of their cancer. 

However, only about one in 10 patients survive for one year.

“CUP is a bit of a pariah because people don’t understand it and assume that nothing can be done. We need to change that attitude and encourage clinicians to look for and treat the drivers of each patient’s disease as shown by DNA profiling,” urged Ross.

An analysis of 303 CUP tissue samples collected in 2018, reported at the ESMO Congress 2019, used cutting edge technology to search for DNA changes and revealed that 32% could have been targeted by the latest medicines.

The same technology is now being used in the ongoing prospective CUPISCO trial.

This is randomising patients with CUP to individualised targeted treatment or immunotherapy based on genetic alternations in their tumour, or to standard platinum-based chemotherapy.

Initial results are expected within the next few years.

The need for a greater understanding of CUP tumour biology and a wider range of targeted therapies is reinforced by results of the GEFCAPI 04 trial, also reported at the ESMO Congress 2019.

Started in 2012, this study used gene expression technology to identify the most likely primary tumour source in patients with CUP.

However, best available targeted and other treatment tailored to primary tumours failed to improve disease progression or survival compared to standard platinum–based chemotherapy.

“The GEFCAPI 04 results are disappointing but many of the patients had pancreatic, biliary and other kinds of cancer which are extremely difficult to treat and for which there are no targeted treatments. In a small number of patients who had suspected primary cancers unlikely to respond to empiric chemotherapy, molecular testing allowed use of a targeted agent or better tailored chemotherapy or immunotherapy. But there were probably not enough to make a difference to the overall results of the study,” said study first author Prof Karim Fizazi, Institute Gustave Roussy, University of Paris Sud, Villejuif, France.

“We need better tests, especially for the worst types of cancer, that not only tell us the identity of each patient’s primary tumour but also the detailed biology of their cancer and the potential targets for treatment. In addition, we need better weapons with which to attack those targets. It’s not enough to know what the targets are, we need to be able to do something about them,” concluded Fizazi.

Commenting on the results of the two presentations, Dr Harpreet Wasan, Hammersmith Hospital, Imperial College London, UK, underlined the importance of understanding the fundamental biology of CUP, and not just the origin of the primary tumour.

“Classifying CUP on the basis of a test that is pointing to its site of origin is not enough to improve patient outcomes. These are nasty tumours that behave much more aggressively and spread much earlier than a typical tumour that is diagnosed with a clear primary site. We therefore need a better understanding of the biology that is driving CUP in the sites where it is found rather than where it started, so we can choose the most relevant targeted therapy,” said Wasan.

“We now know that a third of patients with CUP could get tailored treatment that is already available. We don’t yet know if this approach improves their outcomes and that is what the very important CUPISCO trial is designed to show. For clinicians today, there is still significant value in rapidly testing for the site of origin with modern approaches in patients with suspected CUP in case there is a primary tumour that has been missed, especially in general hospitals where more complex testing is not available. This has been demonstrated as being practical in the GEFCAPI 04 trial, despite the disappointing survival results. The diagnosis is very important from a patient’s perspective as those with CUP are amongst the most vulnerable we see. However, for the future, as DNA profiling becomes more widely available and the range of targeted therapies increases, we can hopefully expect a more positive outlook for patients with CUP,” he added.

Source: ESMO