FORCE’s eXamining the Relevance of Articles for Young Survivors (XRAYS) program is a reliable resource for breast cancer research-related news and information. XRAYS reviews new breast cancer research, provides plain-language summaries, and rates how the media covered the topic. XRAYS is funded by the CDC.
Men with breast cancer
Triple negative breast cancer
Her2+ breast cancer
People with a genetic mutation linked to cancer risk
Breast cancer survivors
Women under 45
Women over 45
Healthy people with average cancer risk
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)
|At a glance||In-depth|
|Clinical trials||Resources and references|
|Questions for your doctor|
Understanding how chemotherapy given before breast cancer surgery (neoadjuvant) may trigger metastasis, the spread of cancer to other parts of the body.
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:
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.
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.
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 observation that TMEM activity increased while tumor size decreased suggests that for some breast cancers, neoadjuvant treatment may increase their ability to metastasize.
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.
Daily Mail UK
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.
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.
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.
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.
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 observation that TMEM scores increased while tumor size decreased suggests that for some breast cancers, neoadjuvant treatment may increase metastatic potential.
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.
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.
Share your thoughts on this XRAYS article by taking our brief survey.
FORCE Portal: Metastatic Breast Cancer
Cancer treatment: Breast cancer treatment
Be Empowered Webinar: Newly Diagnosed with Breast Cancer: What You Need to Know
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-27. J 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 therapies. Oncogene. 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.