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Under the Microscope: Closing the Door on Metastasis

Although surgery, radiation and adjuvant therapy given after surgery cures many breast cancers, survivors still live with the fear that their cancer may recur and spread to other parts of the body. These recurrences, which may happen years after the original diagnosis and treatment, are often incurable.

Today, doctors use a variety of prognostic factors to try to determine the likelihood of cancer recurrence. They also use predictive factors, which help determine which adjuvant therapies to use. Adjuvant therapies can include chemotherapy and hormonal therapy, the latter of which may be continued for up to 10 years after surgery. However, prognostic and predictive factors don’t reflect the intrinsic potential of a cancer to spread to other organs, or metastasize. This can lead doctors to recommend treatments that are harsher than necessary and cause patients to suffer side effects they might otherwise avoid.

Joseph Sparano, M.D., associate director for clinical research at the Albert Einstein Cancer Center, has discovered new biomarkers—essentially, warning signs hidden within tumors—that could better predict which breast cancer patients are likely to experience recurrence and metastasis. This information could help doctors identify who would benefit most from specific treatments. Sparano and his collaborators are also testing a new treatment that might help stop cancer from spreading.

“A vast majority of approaches for treating cancer are related to killing cancer cells,” said Sparano. “Our tactic is different because we are identifying what makes cancer deadly—its ability to metastasize and spread to other organs.”

Understanding how cancer spreads

The new work is based on the earlier discovery of tiny structures that act like a gateway to allow tumor cells to enter the blood stream and spread to other parts of the body. This structure, called the tumor microenvironment of metastasis (TMEM), is a site where invasive tumor cells are in direct contact with the cells that line blood vessels and with special immune cells known as macrophages.

“My collaborator, John Condeelis at the Albert Einstein College of Medicine, discovered TMEMs using new methods he developed to track the metastatic process in living animal systems,” said Sparano. “The Condeelis lab then partnered with clinical pathologists to develop a test that could identify and count these TMEMs in a primary breast cancer sample in only five minutes.”

With V Foundation support, Sparano used the new test to evaluate whether TMEMs could serve as a predictive biomarker in a group of 600 patients with early stage breast cancer who received surgery, radiation and adjuvant therapy. The study revealed that the number and density of TMEMs could be used to identify, with greater precision than previously available, who was more likely to have a recurrence in other organs years after diagnosis.

“We also found that breast cancer tumors that were triple negative or HER2 positive had higher TMEM density,” said Sparano. “Since these are known to be more aggressive cancers, this finding is consistent with our observation that the TMEM density is related to the likelihood of the cancer spreading.”

Turning the tables on TMEMs

The researchers are currently evaluating a drug called rebastinib that could potentially prevent cancer cells from entering the blood at the TMEM sites. They are now wrapping up a clinical trial that combines rebastinib with conventional chemotherapy. Based on early positive results of the clinical trial, the company that makes rebastinib launched a larger study to confirm the results.

The team’s investigations have also shown that as tumors shrink in response to chemotherapy, TMEM density increases. This might be a previously unrecognized mechanism of chemotherapy resistance—and a new opening to fight back with drugs that can block this process by keeping TMEMs in check.

A multidisciplinary effort

Sparano notes that working with a multidisciplinary team was critical to his team’s ability to translate biological insights into therapeutics and biomarkers that can be used in the clinic. The team includes basic scientists studying the fundamental mechanisms of metastasis, epidemiologists who study diseases within populations of people, and oncologists who care for patients.

Sparano said the V Foundation funding helped his team lay the groundwork to further study TMEM biomarkers together with another metastasis biomarker called MENA. The researchers hope to find out whether a combined score that integrates TMEM and MENA could predict recurrence with greater precision.