What is Metastatic Cancer? by Susan R. Peck, M.D.

In May 1999, Ann Pendley, then a 44-year-old speech and language therapist in Fort Collins, Colo., found a lump in her breast during a self-exam. Even though nothing had shown up on her latest mammogram and her doctor waved it off, Pendley insisted on getting a biopsy, which identified an aggressive cancer. She immediately had a lumpectomy and, when the surgeon couldn’t get clean margins, a mastectomy. After more than six months of chemotherapy, she was declared disease-free.

In 2004, after a routine scan, Pendley was told her cancer had metastasized to her lungs. The multiple spots were kept under control with chemotherapy. Then, in November 2011, tumors were found in her brain and bones. The brain tumors responded well to directed radiation therapy, but Pendley is doing research and talking to her oncologists about next steps.

Ann Pendley has been living with metastatic breast cancer since 2004.

“Now that it has spread past the blood-brain barrier, it’s a whole new ball game,” she says. She deals with a lot of paperwork, her insurance rates have gone up and she is using specialty pharmacies for drugs she can’t get locally. She hopes to sell her therapy practice to make life a bit easier, but that could leave her without coverage.

Such is life with metastatic disease. But for Pendley, it is life.

“I could be around for a while,” she says. “For years, I kept thinking, I don’t have to worry about that, I’ll be gone by then. But I’m not.”

What is Metastatic Disease?

Metastatic disease is cancer that has spread from the place in the body where it first started to one or more places. The resulting tumors are called metastatic tumors or metastases.

A primary tumor the size of a grape contains a billion cells, and more than a million of them may enter the circulatory system every day, says Isaiah Fidler, PhD, director of the Metastasis Research Laboratory at M.D. Anderson Cancer Center. Only a few of those cells survive and fewer still are believed capable of spreading. But a few may be all it takes

While each cancer metastasizes in its own unique way, the most common sites for metastases to occur are the lungs, bones and liver. Some types of primary tumors seem more prone to metastasis, and certain cancers tend to spread to specific locations—breast cancer to the lungs and liver, for example, and prostate cancer to the bones and lungs. The majority of metastatic tumors land in the first capillary bed beyond the primary tumor, says Patricia Steeg, PhD, chief of the Women’s Cancers Section at the National Cancer Institute, but 30 percent don’t follow this pattern. Interaction between the tumor cell and potential host organ plays a key role; just as not all tumor cells are capable of metastasizing, not all organs can sustain one.

A cancer that spreads to another part of the body is still considered the original type of cancer—colon cancer that spreads to the liver is still colon cancer, for example, and is usually treated with drugs used for colon cancer.

How Is Metastasis Detected?

Many patients have evidence at initial diagnosis that tumor cells have spread beyond the primary site, Steeg says. This may be a reflection of when certain types of cancer are caught. “For example, we’re bad at finding early-stage ovarian or pancreatic cancer, so when we find it, it has had a lot of time to metastasize,” she says. “In theory, though, in the lab there are cancers that seem prone to metastasize and those that don’t.”

Detection of metastasis varies from one type of cancer to another, says George W. Sledge Jr., MD, an oncologist in Indianapolis. A high percentage of metastases are diagnosed because an individual experienced symptoms. In the case of breast cancer, monitoring asymptomatic patients for recurrence with blood tests and scans actually does not appear to improve outcomes and is generally not recommended, but evaluations of symptoms should be pursued by appropriate scanning.

If you’re having a symptom and it gradually gets worse, that is absolutely, positively a reason to contact your physician and be evaluated. —George W. Sledge, Jr., MD

“Vigilance on the part of the patient is appropriate, and part of the discussion to have with your physician post-treatment is what you should be looking for,” he says. Two key words for symptoms are persistent and progressive. “When a cancer comes back, you tend to have the same symptoms day after day in the same place, and they tend to get worse over time.”

That was the case for Maria Wetzel, 67, a retired clinical laboratory specialist in Michigan who received a diagnosis of stage 2 invasive ductal carcinoma in 1996 and was treated for recurrence in 2004. About five years later, she noticed shortness of breath, which continued to worsen. Imaging tests confirmed metastatic disease in her lungs and liver.

“If you’re having a symptom and it gradually gets worse, that is absolutely, positively a reason to contact your physician and be evaluated,” Sledge stresses. “As a general rule of thumb, if it is enough to worry the patient, it ought to be enough to worry the doctor.”

For some cancers, the American Society of Clinical Oncology (ASCO) recommends routine follow-up testing to detect metastasis. This testing can include blood tests for high levels of carcinoembryonic antigen (ASCO recommends this for stage 2 and 3 colon cancer, for example), abnormal hormone levels or other markers; periodic imaging scans; and physical exams. Both of Pendley’s recurrences showed up in routine scans.

Treating the Spread

Although metastatic tumors maintain many of the attributes of the original tumor, there can be key differences, including different mutations and gene expression profiles, and, of course, a different environment from the primary site. While surgery can eliminate many primary tumors, and cancer treatments using medical therapies inhibit tumor growth, additional treatments may be needed to address the metastatic process.

In theory, it would be easier to prevent metastasis than to treat it. “To shrink an already established metastatic tumor, you have to kill billions of tumor cells,” Steeg says, “but to prevent the outgrowth, you only have to get a few cells.” This is the principle underlying the use of adjuvant therapy—that is to treat the individual who has had complete removal of the primary tumor, but in whom there is a high risk of cancer recurrence and spreading. Even with full adjuvant therapy, unfortunately, the risk of metastasis is lowered, but cancer can still spread. Moreover, the effectiveness of adjuvant therapy, as well as the best drugs to use, varies from cancer types and subtypes.

We have to take care of the seed, learn about the soil that it likes and target both. Something that does that will probably be our best therapeutic. —Aline Betancourt, PhD

Effectively preventing or treating metastatic cancer requires understanding the relationship between cancer cells and their environment. The seed and soil hypothesis, first proposed in 1889 by Stephen Paget and later verified through modern research, theorizes that metastatic tumor cells (the “seeds”) need to find favorable microenvironments (the “soil”) in order to thrive.

“We have to take care of the seed, learn about the soil that it likes and target both,” says Aline Betancourt, PhD, research associate professor at the Tulane Center for Stem Cell Research and Regenerative Medicine in New Orleans. “Something that does that will probably be our best therapeutic.”

Regardless of the therapy, though, given the variety of types of cells in a tumor, and the vast quantity of them, some of those cells inevitably prove resistant to it, Fidler says. Over time, the cells that are resistant to treatment replace those that aren’t.

This resistance can be very disease-dependent, Sledge says. Cancer of the prostate, and leukemias and lymphomas, for example, have high survival rates, he says. “With most solid cancers, however, we’re not very good at curing metastatic disease. Our goals shift from the primary goal of cure to the goal of prolonging life, managing symptoms and maintaining quality of life.” The approach becomes long-term management and fortunately, for the most part, as one treatment stops working, something different is available.

“As we get better at identifying those mechanisms of resistance, we’ll become better at overcoming them,” Sledge adds. “It’s like a criminal trying to escape town. The cops throw up a roadblock, and if all the criminal has to do is turn around and leave by a different route, it won’t take him long to get out of town. It’s a matter of throwing up a sufficient number of roadblocks in strategic places.”

Creating those roadblocks and identifying strategic places to put them are huge challenges. Meanwhile, those with metastatic disease wonder where the bad guys will show up next.

Living with this uncertainty becomes the new normal. “With metastatic disease, you really don’t know,” Pendley says. “I didn’t think I’d still be here now. But you just keep showing up.”

In August, Pendley joined a phase 2 trial for GRN1005, a chemotherapy drug that uses the LRP-1 pathway to cross the blood-brain barrier and target tumors in the brain. So far, it seems to be working.

“I may not die of cancer,” she says. “I may die of running off the road on my mountain bike.”


December 7, 2012