Behind cancer of unknown primary: Molecularly-informed stratification and treatment

Behind cancer of unknown primary: Molecularly-informed stratification and treatment

Cancer of unknown primary (CUP) is defined as a metastatic tumor disease for which a standardized work-up is not able to identify a corresponding primary tumor. The underlying biological mechanism remains unclear, which hinders effective treatment. The hypothesis that respective primary tumors were more susceptible to the hosts’ immune system leading to their destruction is one possible explanation. Patients’ prognosis is dismal and treatment options are often limited to systemic therapy. Traditionally, platinum-based chemotherapy represents the standard treatment choice. Previous guidelines estimated that approximately 85% of all CUP patients fall into an unfavorable subset with a median overall survival of only several months1. The other 15% do belong to specific subsets that have better prognosis and additional treatment options.

To start a project in this fluid knowledge environment was an exciting experience right from the beginning. We profited heavily from the interprofessional structure of our multicenter research environment. Working with committed experts from a range of professional backgrounds including biologists, bioinformaticians and medical doctors proved invaluable. Working in close contact enabled us to progress beyond our respective perspectives.  We used data from the German MASTER program conducted by the National Center of Tumor Diseases (NCT), the German Cancer Consortium (DKTK) and the German Cancer Research Center (DKFZ). MASTER is a platform based on which patients can receive molecularly-informed therapy recommendations by combining whole exome/genome sequencing, transcriptome and methylome analysis in a clinical workflow.

We assessed the clinical response of 70 CUP patients from MASTER which were partially treated with recommendations made by a molecular tumor board (MTB) based on whole genome/ exome sequencing and transcriptome analysis. Simultaneously, we analyzed the molecular landscape of these patients. We saw that patients did benefit from treatment with moleculary-informed therapies based on MTB recommendations, which was demonstrated by improved progression free survival in comparison to previous systemic therapies and in comparison to other systemic therapies that were applied after the MTB but not recommended by it.

In our clinical analysis, we demonstrate that molecularly-guided therapies can assist in prolonging patients progression free survival. Consequently, the availability of molecular targets might increase the number of patients that can be categorized as favorable subset dramatically. Personalized approaches targeting specific molecular alterations have not been addressed in prospective clinical trials for CUP patients.  At this point, there is an urgent need for prospective and randomized clinical trials to further investigate possible benefits. Particularly, molecularly-stratified basket trials will hopefully provide further insight3.

Currently, CUP treatment stratification is heavily based on clinical and histopathological information. To assist immunohistopathological subset stratification, we created an entity identifier combining genomic, transcriptomic and methylome-based data trying to assist immunohistopathological subset stratification. Since there is no gold standard in assigning CUPs their tissue of origin due to the fact that there is no primary tumor at the time of diagnosis we could determine its effectiveness only indirectly by using the algorithm to determine the tissue of origin in cancers with a known primary tumor. We believe that utilizing such a classifier in a clinical workflow such as MASTER may benefit the detection of specific subgroups and therefore patients with elevated survival probability and potential site-specific therapy options. Nevertheless, this approach is limited by the sensitivity of our algorithm and in the end by the number of patients harboring a tumor with a molecular landscape assignable to a specific subgroup. In fact, none of the previous trials following a site-specific approach were able to demonstrate a clinical benefit for CUP patients2. Still, we think that the development and careful validation of new methods like ours might be beneficial for CUP patients in the future.

In summary, our data suggests that molecular analysis might allow us to enlarge the favorable subset and may finally lead to a better prognosis in patients with CUP. Therefore, molecular analysis should be made available to all CUP patients.

References

1          Fizazi, K. et al. Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 26 Suppl 5, v133-138, doi:10.1093/annonc/mdv305 (2015).

2          Rassy, E. et al. The role of site-specific therapy for cancers of unknown of primary: A meta-analysis. Eur J Cancer 127, 118-122, doi:10.1016/j.ejca.2019.12.016 (2020).

3          Ross, J. S. et al. Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Origin: Retrospective Molecular Classification Considering the CUPISCO Study Design. Oncologist 26, e394-e402, doi:10.1002/onco.13597 (2021).