Symposium and live panel tap experts to discuss treatment of metastases

In order to improve the survival and quality-of-life in patients with metastatic cancer, more knowledge is needed to understand the hallmarks of and mechanisms underlying metastasis.

The major symposium Options and Opportunities for Treating Metastasis discussed those issues. The symposium is available now as an On Demand session, and the related live panel discussion will take place Thursday, April 15 from 11:30 a.m. – 12 p.m. EDT. To submit a question, watch the On Demand session before the live panel starts and submit a question in the Q&A box to the right of the video window. All questions will reach the panelists.

Hallmarks of metastasis

Danny R. Welch, PhD
Danny R. Welch, PhD

“We cannot effectively treat that which we don’t understand,” said session moderator Danny R. Welch, PhD, University of Kansas Cancer Center.

That is why it is important to understand the hallmarks of metastasis, which include motility and invasion, modulation of the microenvironment, plasticity, and colonization of secondary sites. Metastasis occurs through a number of routes. All are relevant, and there is interconnectivity, but Welch focused his talk on hematogenous metastasis.

During their migration, cancer cells interact with the extracellular matrix, and stiffness varies by tissue and age. Early cells migrate and change the orientation of the matrix and create “highways” allowing for a more rapid movement. There is also recruitment of inflammatory cells that promote invasion. Tumor cells passively follow inflammatory cells, showing that tumor cells are interacting with host cells and showing that possibility exists that this interaction could be disrupted and targeted for therapy.

Later, the cells get into the blood stream and disseminate, Welch said. The cancer cells will later morph during transit, exhibiting cell plasticity. The question remains whether that process occurs at the beginning or at the end when the cells find themselves in different tissues. Once they arrive at a location, they extravasate by being highly deformable.

Studies have shown that there are pro-metastatic genes, but also metastasis suppressors that block metastasis without blocking the primary tumor growth.

“This is genetic proof the metastasis is a distinct phenotype from primary tumors,” Welch said. “It is critical with that knowledge that primary tumors and metastasis cannot and should never be treated equivalently.”

Evolution of metastasis

Samra Turajlic, MBBS, PhD
Samra Turajlic, MBBS, PhD

Samra Turajlic, MBBS, PhD, Francis Crick Institute, discussed the clonal evolution of metastasis. Turajlic and colleagues have looked at the timing and emergence of metastasis competence. Tumors that do not acquire any chromosomal complexity or instability appear to be incompetent of forming metastases, Turajlic said.

Also, the tumors that present with oligometastatic disease acquire metastatic competence, with high-risk loci events fairly late in tumor evolution, and characterize only a minority of cells within the primary tumor.

In cases where there is an explosion of metastatic disease, the high-risk loci and chromosomal instability are, in general, fixed early on and are clonally dominant in the primary tumor.

To illustrate this, she discussed two patient examples. One patient had metastatic disease at presentation and poor prognosis with overall survival of less than 6 months from diagnosis. There was early fixation of high-risk events and dominance of the clone at the primary tumor site. Every single metastatic site, irrespective of tissue, was seeded by this dominant clone.

In contrast, the second patient presented with localized disease with slow dissemination, surviving for 17 years from diagnosis. Most metastasis were seeded by a clone that was a minor clone at the primary tumor site, with other metastases arising from another clone.

Turajlic also discussed how chromosomal instability and whole genome doubling appear to facilitate disease progression and potentially treatment resistance, but this needs functional validation, she said.

Options and opportunities

Ralph R. Weichselbaum, MD
Ralph R. Weichselbaum, MD

Ralph R. Weichselbaum, MD, University of Chicago, discussed how metastases represent a spectrum.

Weichelbaum highlighted a study that showed that molecular subtypes complement clinical risk stratification. In a study of 134 patients with limited liver metastases from colorectal cancer, molecular analysis of limited de novo liver metastases was performed, and a 113-gene signature was created. The signature was validated in an independent Memorial Sloan Kettering Cancer Center dataset. This validation showed that, for example, patients with an immune AA phenotype did very well. This means that gene expression ultimately should inform prognostication and therapy.

Weichselbaum also summarized several clinical trials that show that the reality of metastases is that they are truly a spectrum. He also highlighted some of the strategies being used to treat advanced cancers.