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Can chemotherapy before surgery fuel breast cancer metastasis?


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Some breast cancer patients are given neoadjuvant (before surgery) chemotherapy. However, some recent studies have raised concerns that neoadjuvant treatment might actually trigger cancer spread in certain situations. In the current study, researchers used mouse models and human breast cancers to explore this possibility. (10/10/17)


STUDY AT A GLANCE

This study is about:

Understanding how chemotherapy given before breast cancer surgery (neoadjuvant) may trigger metastasis, the spread of cancer to other parts of the body.

Why is this study important? 

One way doctors treat breast cancer is to use chemotherapy before surgery, and then surgically remove the patient’s remaining tumor after chemotherapy. This is known as neoadjuvant treatment. The goal of this type of treatment is to weaken and destroy the cancer. Neoadjuvant chemotherapy isn't routinely used to treat early-stage breast cancer. It is used under the following conditions:

  • when there is concern that the cancer might spread during the time between the initial diagnosis and the time when treatment begins after recovery from surgery.
  • to shrink tumors, making them easier to surgically remove.
  • to allow doctors to see if the tumor responds to chemotherapy which helps them get a sense of whether the treatment worked well, whether any future chemotherapy should be given and if so, whether the same or a different kind should be used. 

Recently, some studies have suggested that certain chemotherapy drugs used in a neoadjuvant setting may trigger cancer cells to metastasize. Currently, scientists believe that in order for metastasis to occur, three types of cells must come together in the same spot: tumor cells, immune cells and endothelial cells (cells which line organs such as blood vessels). These spots, called "tumor microenvironments of metastasis” or “TMEMs” are found on blood vessels within tumors and can act like “on-ramps” allowing cancer cells into blood vessels where they can spread to other parts of the body including lungs, bones, and brain.  This video may help you better understand the complicated process.

Study Findings

Three standard chemotherapies used as neoadjuvant treatment for breast cancer—paclitaxel, doxorubicin, and cyclophosphamide—were examined in mouse models and tumor tissue from human breast cancer patients to study whether neoadjuvant chemotherapy can trigger metastasis.

  • In mice with breast cancer who were treated with paclitaxel:
    • More immune cells were found at TMEM sites.
    • More active tumor cells were found at TMEM sites.
    • Blood vessels at TMEM sits were leakier or open to cancer cells to enter.

As a result, mice treated with neoadjuvant 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 altered 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 increased in residual disease.

The observation that TMEM activity increased while tumor size decreased suggests that for some breast cancers, neoadjuvant treatment may increase their ability to metastasize.

What does this mean for me?

If your health care provider is recommending neoadjuvant chemotherapy, it is important for you to know the risks and benefits of treatment before surgery. It is also important to understand that neoadjuvant chemotherapy has not been proven to increase the chances of metastasis in breast cancer patients. Not all breast cancers are the same and neoadjuvant chemotherapy might have different effects on the risk for metastasis for other breast cancer subtypes. A recently developed lab test can be done to tell if a patient’s tumor is more likely to metastasize from neoadjuvant treatment. While this test is available for clinical use in most states, it is not routinely done. 

If you and your health care provider determine that neoadjuvant chemotherapy is right for you, you may also want to discuss a current clinical trial being conducted by the researchers involved in this study.  This study is looking at an experimental compound called rebastinib, being developed by Deciphera Pharmaceuticals (the researchers have no financial ties to Deciphera Pharmaceuticals) which appears to block TMEM assembly and function in preliminary experiments. This clinical trial is recruiting patients with metastatic ER-positive/HER2-negative breast cancer.

Questions to ask your health care provider:

  • What are the benefits and risks of neoadjuvant chemotherapy prior to surgery?
  • Should I consider having a lab test that might show if my tumor has the potential to spread due to neoadjuvant chemotherapy?  

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 survival2,3.
  • 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 angiogenesis4-8.  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

References

Current Study:

Karagiannis GS, Pastoriza JM, Wang Y, Harney AS, Entenberg D, Pignatelli J, Sharma VP, Xue EA, Cheng E, D'Alfonso TM, Jones JG, Anampa J, Rohan TE, Sparano JA, Condeelis JS, Oktay MH. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. Sci Transl Med. 2017.  9(397).

1. Rohan TE, Xue X, Lin HM2, D'Alfonso T2, Ginter PS, Oktay MH, Robinson BD, Ginsberg M, Gertler FB, Glass AG, Sparano JA, Condeelis JS, Jones JG.  Tumor microenvironment of metastasis and risk of distant metastasis of breast cancer.  J Natl Cancer Inst. 2014.  106(8).

2. Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27J Clin Oncol. 2008.  26(5):778-85.

3. Gianni L1, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Cussac AL, Bozhok A, Martinez-Agulló A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna GJ.  Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol. 2009. 

4. Daenen LG, Houthuijzen JM, Cirkel GA, Roodhart JM, Shaked Y, Voest EE. Treatment-induced host-mediated mechanisms reducing the efficacy of antitumor therapiesOncogene. 2014.  33(11):1341-7. 

5. De Palma M and Lewis CE.  Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell. 2013.  23(3):277-86.

6. Hughes R, Qian BZ, Rowan C, Muthana M, Keklikoglou I, Olson OC, Tazzyman S, Danson S, Addison C, Clemons M, Gonzalez-Angulo AM, Joyce JA, De Palma M, Pollard JW, Lewis CE.  Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy Cancer Res. 2015. 75(17):3479-91.

7. Shaked Y, Ciarrocchi A, Franco M, Lee CR, Man S, Cheung AM, Hicklin DJ, Chaplin D, Foster FS, Benezra R, Kerbel RS.  Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science. 2006. 313(5794):1785-7.

8. Shaked Y, Henke E, Roodhart JM, Mancuso P, Langenberg MH, Colleoni M, Daenen LG, Man S, Xu P, Emmenegger U, Tang T, Zhu Z, Witte L, Strieter RM, Bertolini F, Voest EE, Benezra R, Kerbel RS. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell. 2008. 14(3):263-73.

9. Harney AS, Arwert EN, Entenberg D, Wang Y, Guo P, Qian BZ, Oktay MH, Pollard JW, Jones JG, Condeelis JS.  Real-Time Imaging Reveals Local, Transient Vascular Permeability, and Tumor Cell Intravasation Stimulated by TIE2hi Macrophage-Derived VEGFA.  Cancer Discov. 5(9):932-43.

10. KaragiannisGS, Goswami S, Jones JG, Oktay MH and Condeelis JS.  Signatures of breast cancer metastasis at a glance.  J Cell Sci. 2016. 129(9): 1751–1758.

Clinical Trial: 

Rebastinib Plus Antitubulin Therapy With Paclitaxel or Eribulin in Metastatic Breast Cancer

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