Study: Can chemotherapy before surgery fuel breast cancer metastasis?

IN-DEPTH REVIEW OF RESEARCH

Study background:

Breast cancer cells can metastasize through microscopic sites called tumor “microenvironment of metastasis” (TMEM). Each TMEM site is composed of three different types of cells that are in direct contact with each other:  tumor cells, immune cells, and endothelial cells that line organs like blood vessels.  The hypothesis is that TMEMs are sites on blood vessels to which special immune cells flock. These sites act as “on-ramps” into the blood vessels allowing potential spread of the cancer cells. Certain chemotherapy drugs may affect these “on-ramps to the highways of metastasis,” said biologist John Condeelis of Albert Einstein College of Medicine, senior author of the current study. If the immune cells contact a tumor cell, they usher it into a blood vessel like a taxi picking up a passenger. Blood vessels then act like highways, transporting the taxi (immune and tumor cells) beyond the breast. They illustrate this concept in this video. Scientists believe this is how tumor cells migrate to distant organs, including the lungs, bones and brain.

Clinically, TMEMs are used as a marker of metastatic potential; the density of TMEMs correlates with metastatic outcomes in breast cancer patients¹. George Karagiannis and colleagues at the Albert Einstein College of Medicine hypothesized that neoadjuvant chemotherapy may increase the density of TMEM sites and the activity of cells at those sites. Because TMEM sites are a combination of tumor, immune, and blood vessel cells, evidence of an increase of all three cells and an increase in their activity is needed to show their hypothesis may be true. Results from previous studies provided some evidence to support this hypothesis.

• Although studies have shown that using paclitaxel as a neoadjuvant therapy before surgery increases the rate of pathological complete response—no active cancer cells are present following treatment—neoadjuvant treatment has not been shown to improve overall survival^2,3.
• Other studies have shown that some chemotherapies promote tumor growth by increasing the formation of new blood vessels within the tumor, a process known as angiogenesis^4-8.  While angiogenesis is necessary for tumors to grow, it is not enough for tumor cell metastasis, which also requires tumor cells to become mobile with the help of immune cells. 
• Paclitaxel has been shown to cause immune cells to migrate into primary breast tumors⁹.

They tested this hypothesis using mouse models and pre- and post-neoadjuvant chemotherapy breast cancer tissue samples from human patients, and described their results in Science Translational Medicine in July, 2017.

Researchers of this study wanted to know:

Does neoadjuvant chemotherapy promote metastasis at TMEMs and if so, are there ways to block cells at these sites and decrease a tumor’s metastatic potential.

Population(s) looked at in the study:

• Mouse models: Over three years, the researchers experimented with lab mice whose genetic mutations make them spontaneously develop breast cancer, as well as mice with breast tumors derived from human breast tumors.
• Human tissue: The scientists also analyzed tissue from 20 breast cancer patients who had undergone neoadjuvant chemotherapy (12 weeks of paclitaxel and four of doxorubicin and cyclophosphamide).

Study findings:

Three standard pre-operative chemotherapies for breast cancer—paclitaxel, doxorubicin, and cyclophosphamide—were examined in mouse models and human breast cancers to determine if neoadjuvant chemotherapy can trigger metastasis.

• In mice with breast cancer who were treated with paclitaxel:
  • Tumor cells at TMEM sites became more mobile.
  • More immune cells were found at TMEM sites.
  • Blood vessels at TMEM sits were more permeable.

As a result, mice treated with paclitaxel had twice as many cancer cells in their blood and lungs compared to control mice with breast cancer who did not receive paclitaxel. Similarly, a combination of neoadjuvant treatment with doxorubicin followed by cyclophosphamide also promoted metastasis by altering TMEM sites.

• The researchers also examined breast cancers from 20 patients who underwent neoadjuvant chemotherapy. These patients had ER-positive/HER2-negative disease and were treated with paclitaxel (weekly for up to 12 weeks) followed by 4 cycles of doxorubicin plus cyclophosphamide. All patients still had residual disease (detectable breast cancer) after treatment.
  • In all patients treated with the neoadjuvant regimen:
    • Tumor size decreased.
    • TMEM activity in residual disease increased.

The observation that TMEM scores increased while tumor size decreased suggests that for some breast cancers, neoadjuvant treatment may increase metastatic potential. 

• Finally, the researchers investigated the effect of rebastinib, a TMEM inhibitor, in mouse models.  Mice received neoadjuvant chemotherapy with or without rebastinib. While treatment with rebastinib did not significantly affect overall TMEM activity or the number of immune cells at TMEM sites, rebastinib did significantly reduce the number of circulating tumor cells. This is very early research but indicates the importance of developing ways to reduce the metastatic potential of TMEMs.

Limitations:

This study used mice to understand how neoadjuvant chemotherapy may trigger breast cancer metastasis.  While researchers did study human breast tumors both pre- and post-adjuvant chemotherapy, only 20 patients were included. Drawing conclusions based on research in mice and only a small number of human tumors is difficult. In addition, all of the patients in this study had ER-positive/HER2-negative disease, so it is not known if these results are applicable to other breast cancer subtypes.  Furthermore, the patients in this study were only followed for 5 years. This is not a long enough timeframe to analyze distant recurrence in this subtype. If ER-positive disease recurs, it can be 10 or more years after the initial diagnosis. 

Conclusions:

In order for breast cancer to lead to death it patients, it must spread beyond the breast to other organs. This is known as metastasis. It is critical for researchers to develop treatments that prevent progression of cancer to the metastatic stage and to prevent further spread from existing sites of metastasis. This study provides insight into how neoadjuvant chemotherapy may change the tumor in some breast cancers and promote metastasis. However, much more research is needed to determine whether breast cancer patients who are treated with neoadjuvant chemotherapy prior to surgery are at increased risk of metastasis.  

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Posted 10/10/17