Breast cancer surgery with negative or clear margins, which leaves no signs of cancer behind, stimulates a protective anticancer immune response that reduces the risk of cancer spread to other regions in the body, a mouse study suggests.
Researchers are now studying if the molecular culprits involved in this response in animal models also have a parallel in women with breast cancer.
The study, “Primary tumor-induced immunity eradicates disseminated tumor cells in syngeneic mouse model,” was published in the journal Nature Communications.
After breast cancer surgery, a pathologist uses a microscope to analyze the tissue removed and look for cancer cells at the margins. If no cancer cells are seen at the outer edge of the tissue, the pathologist declares that it has negative or clear margins.
If there are still cancer cells in the edges — considered to have positive margins — it means that some cancer cells may have been left. In this case, usually a surgeon will go back and perform a re-excision, and remove more tissue.
This new study, led by researchers at Georgia Cancer Center in Augusta University, supports the idea that when a breast tumor is removed with clear margins, a patient is less likely to develop metastasis later — that is, to see the cancer spread to other parts of the body.
Evidence indicates that solid tumors send out tumor cells early and continuously, but most of these cells — about 90% — die before establishing themselves elsewhere in the body.
However, a few of these surviving cells can settle at remote places such as the bone marrow, lung, or liver, and give rise to a second tumor. This can happen following surgery, chemotherapy, and/or immunotherapy, or after a patient is in remission. Many times, metastasis becomes apparent years after the initial cancer.
“However, the fate of these early disseminated tumor cells remains elusive,” the researchers wrote.
The mechanisms behind deadly metastasis have been debated among scientists, with many contradictory and puzzling findings.
To better understand what happens at the initial phase of tumor dissemination, and how surgery makes an impact on those first steps, the researchers used mouse models to mimic the spread of breast cancer.
They used two different models, one to simulate a very aggressive cancer, such as triple negative breast cancer in women, and another to replicate a less invasive breast tumor.
In both models, tumor cells had disseminated within a week into the lymph nodes that drain the breasts of the mice and into their lungs, also common sites for breast cancer spread in women.
However, mice with more aggressive cancer quickly developed deadly metastasis, while those with a less aggressive cancer were able to clear off the cells shed from the original tumor.
A key observation of the study was that after surgery to completely removed the primary tumor, mice stopped developing detectable metastasis and were also able to reject injected tumor cells.
It became apparent that such effective antitumor response was possible due to a type of immune system attackers called cytotoxic T cells — specialized cells that can directly kill cancer cells. If these cells were removed from mice, the cancer would spread rapidly.
In fact, it looked like the immune system remembered how to attack the tumor spread for as long as six months, as after this time a similar antitumor response was still in place.
In contrast, the researchers noted that if a portion of the primary tumor was left behind after surgery, an opposite response prevailed. Immune cells called myeloid-derived suppressor cells — which taper immune responses of T-cells — move in to other areas where the tumor cells have spread to, thereby supporting their growth and settlement.
Moreover, the levels of protective cytotoxic T-cells decreased during this process.
A small molecule that circulates in the blood also seems central to the process, a white blood cell growth factor called granulocyte-colony stimulating factor (G-CSF).
When mice with less aggressive cancers were manipulated to get more G-CSF, the antitumor immune response was suppressed, more myeloid-derived suppressor cells migrated to the places of tumor spread, and metastasis was promoted.
The researchers believe that when surgery successfully removes all of the breast tumors (when there are clear margins), the procedure itself brings on an inflammatory response that invigorates the fight against the cancer.
On the other hand, when part of a tumor is left behind, there is somewhat of an inverse effect where the immune system acts as a friend of the tumor rather than its foe.
The researchers wrote that their findings “provide a compelling evidence for the immune-mediated eradication of DTCs [disseminated tumor cells] following the complete resection of primary tumors.”
“Furthermore, our studies may also provide molecular explanation of improved overall survival in breast cancer patients following complete resection of primary tumors with negative margins,” they added.
The researchers are now collecting blood samples from breast cancer patients to look at the levels of G-CSF, in an effort to find a possible connection between worse outcomes and elevated levels of this factor, Hasan Korkaya, DVM, PhD and senior author of the study, said in a press release. Korkaya is a tumor biologist at the Georgia Cancer Center at the Medical College of Georgia, Augusta University.
Also, the scientists said that what they found in their breast cancer model could be applied to other solid cancers treated by surgery.