82O - Genomic evolution of metastatic tumours under therapeutic pressure

Background

Whole genome sequencing (WGS) is a powerful tool to swiftly and comprehensively identify personalized anticancer treatment options. However, in metastatic cancer, the extent to which somatic genomic profiles are preserved between lesions (heterogeneity in space) and over the course of a patient’s anticancer treatment (heterogeneity in time) remains unclear. Clinicians need guidance on the necessity to repeat genomic characterization in patients with cancer in order to efficiently maximize treatment opportunities.

Methods

WGS data was prospectively collected of 497 longitudinally sampled biopsies from 239 metastatic cancer patients with tumours from 21 different primary sites. Biopsies were taken prior to and after various types of systemic treatments. Available clinical data was used to study associations between the evolution of somatic genomic profiles and clinical characteristics.

Results

During the biopsy interval (median 6.4 months, IQR 3.8-9.6 months), there was a statistically significant but modest (median <10%; mean <20%) increase in the number of mutations, copy number alterations, structural variants and indels. Genomic biomarkers for standard-of-care treatments and clinical trial enrolment could be identified in 22% (n=107) and 51% (n=253) of biopsies, respectively. For 99% (n = 247) of the sequential pairs, the second biopsy did not yield new information regarding standard-of-care genomic treatment indications. Out of 355 biomarkers for clinical trial enrolment identified in the first biopsies, 326 (92%) were also present in the subsequent biopsy. For 224 out of 250 (90%) paired biopsies, the second biopsy did not yield additional biomarkers for clinical trial enrolment. Twenty-eight of the 81 (35%) patients treated with targeted or hormonal therapy between the biopsies gained somatic variants within the gene directly targeted by the drug, revealing known and novel resistance mechanisms.

Conclusions

Our data demonstrates that a one-time WGS analysis during the disease course of a patient with metastatic cancer is (i) sufficient for identifying standard-of-care genomic biomarkers, and (ii) supportive of revealing investigational therapeutic targets that remain present at later stages of the disease.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Josephine Nefkens Stichting, Hartwig Medical Foundation, Oncode Institute, Center for Personalized Cancer Treatment.

Disclosure

All authors have declared no conflicts of interest.