Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism
Closing the door to cancer cells
Breast cancer is one of the most common tumor types, and metastasis greatly increases the risk of death from this disease. By studying the process of intravasation or entry of cells into the vasculature, Karagiannis et al. discovered that, in addition to killing tumor cells, chemotherapy treatment can also increase intravasation. Groups of cells collectively known as tumor microenvironment of metastasis (TMEM) can serve as gateways for tumor cells entering the vasculature, and the authors discovered that several types of chemotherapy can increase the amounts of TMEM complexes and circulating tumor cells in the bloodstream. The researchers also determined that a drug called rebastinib can interfere with TMEM activity and help overcome the increased risk of cancer cell dissemination.
Abstract
Breast cancer cells disseminate through TIE2/MENACalc/MENAINV-dependent cancer cell intravasation sites, called tumor microenvironment of metastasis (TMEM), which are clinically validated as prognostic markers of metastasis in breast cancer patients. Using fixed tissue and intravital imaging of a PyMT murine model and patient-derived xenografts, we show that chemotherapy increases the density and activity of TMEM sites and Mena expression and promotes distant metastasis. Moreover, in the residual breast cancers of patients treated with neoadjuvant paclitaxel after doxorubicin plus cyclophosphamide, TMEM score and its mechanistically connected MENAINV isoform expression pattern were both increased, suggesting that chemotherapy, despite decreasing tumor size, increases the risk of metastatic dissemination. Chemotherapy-induced TMEM activity and cancer cell dissemination were reversed by either administration of the TIE2 inhibitor rebastinib or knockdown of the MENA gene. Our results indicate that TMEM score increases and MENA isoform expression pattern changes with chemotherapy and can be used in predicting prometastatic changes in response to chemotherapy. Furthermore, inhibitors of TMEM function may improve clinical benefits of chemotherapy in the neoadjuvant setting or in metastatic disease.
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Supplementary Material
Summary
Materials and Methods
Fig. S1. Histological sections of control and paclitaxel-treated mice.
Fig. S2. Macrophage population dynamics in control and paclitaxel-treated mice.
Fig. S3. Microvascular density in control and paclitaxel-treated mice.
Fig. S4. IVI and extravascular dextran intensity analysis.
Fig. S5. Experimental design of in vivo metastasis dissemination assays.
Fig. S6. Frequency of bursting normalized to TMEM sites.
Fig. S7. MENAINV expression at the gene and protein levels.
Fig. S8. The association of Mena isoform expression with TIE2hi/VEGFhi macrophages.
Fig. S9. Macrophage population dynamics after paclitaxel treatment in MENA−/− mice.
Fig. S10. Correlation of TMEM scoring between pathologists.
Table S1. Forward and reverse primer sequences used to identify transmission of the disrupted Mena allele in MENA−/− mice.
Video S1. Bursting close to a TMEM site of a paclitaxel-treated mouse.
Video S2. Bursting close to a TMEM site of a second paclitaxel-treated mouse.
Video S3. Absence of bursting in the vasculature of a paclitaxel-treated mouse.
Resources
REFERENCES AND NOTES
1
A. S. Harney, E. N. Arwert, D. Entenberg, Y. Wang, P. Guo, B.-Z. Qian, M. H. Oktay, J. W. Pollard, J. G. Jones, J. S. Condeelis, Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage–derived VEGFA. Cancer Discov. 5, 932–943 (2015).
2
G. S. Karagiannis, S. Goswami, J. G. Jones, M. H. Oktay, J. S. Condeelis, Signatures of breast cancer metastasis at a glance. J. Cell Sci. 129, 1751–1758 (2016).
3
B. D. Robinson, G. L. Sica, Y.-F. Liu, T. E. Rohan, F. B. Gertler, J. S. Condeelis, J. G. Jones, Tumor microenvironment of metastasis in human breast carcinoma: A potential prognostic marker linked to hematogenous dissemination. Clin. Cancer Res. 15, 2433–2441 (2009).
4
M. H. Oktay, F. B. Gertler, Y.-F. Liu, T. E. Rohan, J. S. Condeelis, J. G. Jones, Correlated immunohistochemical and cytological assays for the prediction of hematogenous dissemination of breast cancer. J. Histochem. Cytochem. 60, 168–173 (2012).
5
T. E. Rohan, X. Xue, H.-M. Lin, T. M. D’Alfonso, P. S. Ginter, M. H. Oktay, B. D. Robinson, M. Ginsberg, F. B. Gertler, A. G. Glass, J. A. Sparano, J. S. Condeelis, J. G. Jones, Tumor microenvironment of metastasis and risk of distant metastasis of breast cancer. J. Natl. Cancer Inst. 106, dju136 (2014).
6
P. Rastogi, S. J. Anderson, H. D. Bear, C. E. Geyer, M. S. Kahlenberg, A. Robidoux, R. G. Margolese, J. L. Hoehn, V. G. Vogel, S. R. Dakhil, D. Tamkus, K. M. King, E. R. Pajon, M. J. Wright, J. Robert, S. Paik, E. P. Mamounas, N. Wolmark, Preoperative chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J. Clin. Oncol. 26, 778–785 (2008).
7
L. Gianni, J. Baselga, W. Eiermann, V. G. Porta, V. Semiglazov, A. Lluch, M. Zambetti, D. Sabadell, G. Raab, A. L. Cussac, A. Bozhok, A. Martinez-Agulló, M. Greco, M. Byakhov, J. J. L. Lopez, M. Mansutti, P. Valagussa, G. Bonadonna, 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. 27, 2474–2481 (2009).
8
L. G. M. Daenen, J. M. Houthuijzen, G. A. Cirkel, J. M. L. Roodhart, Y. Shaked, E. E. Voest, Treatment-induced host-mediated mechanisms reducing the efficacy of antitumor therapies. Oncogene 33, 1341–1347 (2014).
9
M. De Palma, C. E. Lewis, Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23, 277–286 (2013).
10
R. Hughes, B.-Z. Qian, C. Rowan, M. Muthana, I. Keklikoglou, O. C. Olson, S. Tazzyman, S. Danson, C. Addison, M. Clemons, A. M. Gonzalez-Angulo, J. A. Joyce, M. De Palma, J. W. Pollard, C. E. Lewis, Perivascular M2 macrophages stimulate tumor relapse after chemotherapy. Cancer Res. 75, 3479–3491 (2015).
11
J. M. L. Roodhart, H. He, L. G. M. Daenen, A. Monvoisin, C. L. Barber, M. van Amersfoort, J. J. Hofmann, F. Radtke, T. F. Lane, E. E. Voest, M. L. Iruela-Arispe, Notch1 regulates angio-supportive bone marrow–derived cells in mice: Relevance to chemoresistance. Blood 122, 143–153 (2013).
12
Y. Shaked, A. Ciarrocchi, M. Franco, C. R. Lee, S. Man, A. M. Cheung, D. J. Hicklin, D. Chaplin, F. S. Foster, R. Benezra, R. S. Kerbel, Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 313, 1785–1787 (2006).
13
Y. Shaked, E. Henke, J. M. L. Roodhart, P. Mancuso, M. H. G. Langenberg, M. Colleoni, L. G. Daenen, S. Man, P. Xu, U. Emmenegger, T. Tang, Z. Zhu, L. Witte, R. M. Strieter, F. Bertolini, E. E. Voest, R. Benezra, R. S. Kerbel, Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: Implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 14, 263–273 (2008).
14
M. De Palma, M. A. Venneri, R. Galli, L. Sergi Sergi, L. S. Politi, M. Sampaolesi, L. Naldini, Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8, 211–226 (2005).
15
M. De Palma, M. A. Venneri, C. Roca, L. Naldini, Targeting exogenous genes to tumor angiogenesis by transplantation of genetically modified hematopoietic stem cells. Nat. Med. 9, 789–795 (2003).
16
A. Dovas, A. Patsialou, A. S. Harney, J. Condeelis, D. Cox, Imaging interactions between macrophages and tumour cells that are involved in metastasis in vivo and in vitro. J. Microsc. 251, 261–269 (2013).
17
A. Patsialou, J. J. Bravo-Cordero, Y. Wang, D. Entenberg, H. Liu, M. Clarke, J. S. Condeelis, Intravital multiphoton imaging reveals multicellular streaming as a crucial component of in vivo cell migration in human breast tumors. Intravital 2, e25294 (2013).
18
E. T. Roussos, J. S. Condeelis, A. Patsialou, Chemotaxis in cancer. Nat. Rev. Cancer 11, 573–587 (2011).
19
S. Goswami, U. Philippar, D. Sun, A. Patsialou, J. Avraham, W. Wang, F. Di Modugno, P. Nistico, F. B. Gertler, J. S. Condeelis, Identification of invasion specific splice variants of the cytoskeletal protein Mena present in mammary tumor cells during invasion in vivo. Clin. Exp. Metastasis 26, 153–159 (2009).
20
E. T. Roussos, S. Goswami, M. Balsamo, Y. Wang, R. Stobezki, E. Adler, B. D. Robinson, J. G. Jones, F. B. Gertler, J. S. Condeelis, M. H. Oktay, Mena invasive (MenaINV) and Mena11a isoforms play distinct roles in breast cancer cell cohesion and association with TMEM. Clin. Exp. Metastasis 28, 515–527 (2011).
21
E. T. Roussos, M. Balsamo, S. K. Alford, J. B. Wyckoff, B. Gligorijevic, Y. Wang, M. Pozzuto, R. Stobezki, S. Goswami, J. E. Segall, D. A. Lauffenburger, A. R. Bresnick, F. B. Gertler, J. S. Condeelis, Mena invasive (MenaINV) promotes multicellular streaming motility and transendothelial migration in a mouse model of breast cancer. J. Cell Sci. 124, 2120–2131 (2011).
22
J. Wyckoff, W. Wang, E. Y. Lin, Y. Wang, F. Pixley, E. R. Stanley, T. Graf, J. W. Pollard, J. Segall, J. Condeelis, A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 64, 7022–7029 (2004).
23
U. Philippar, E. T. Roussos, M. Oser, H. Yamaguchi, H.-D. Kim, S. Giampieri, Y. Wang, S. Goswami, J. B. Wyckoff, D. A. Lauffenburger, E. Sahai, J. S. Condeelis, F. B. Gertler, A Mena invasion isoform potentiates EGF-induced carcinoma cell invasion and metastasis. Dev. Cell 15, 813–828 (2008).
24
A. Patsialou, J. Wyckoff, Y. Wang, S. Goswami, E. R. Stanley, J. S. Condeelis, Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor. Cancer Res. 69, 9498–9506 (2009).
25
S. Goswami, E. Sahai, J. B. Wyckoff, M. Cammer, D. Cox, F. J. Pixley, E. R. Stanley, J. E. Segall, J. S. Condeelis, Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res. 65, 5278–5283 (2005).
26
E. Leung, A. Xue, Y. Wang, P. Rougerie, V. P. Sharma, R. Eddy, D. Cox, J. Condeelis, Blood vessel endothelium-directed tumor cell streaming in breast tumors requires the HGF/C-Met signaling pathway. Oncogene 36, 2680–2692 (2017).
27
J. Pignatelli, J. J. Bravo-Cordero, M. Roh-Johnson, S. J. Gandhi, Y. Wang, X. Chen, R. J. Eddy, A. Xue, R. H. Singer, L. Hodgson, M. H. Oktay, J. S. Condeelis, Macrophage-dependent tumor cell transendothelial migration is mediated by Notch1/MenaINV-initiated invadopodium formation. Sci. Rep. 6, 37874 (2016).
28
E. T. Roussos, Y. Wang, J. B. Wyckoff, R. S. Sellers, W. Wang, J. Li, J. W. Pollard, F. B. Gertler, J. S. Condeelis, Mena deficiency delays tumor progression and decreases metastasis in polyoma middle-T transgenic mouse mammary tumors. Breast Cancer Res. 12, R101 (2010).
29
J. Pignatelli, S. Goswami, J. G. Jones, T. E. Rohan, E. Pieri, X. Chen, E. Adler, D. Cox, S. Maleki, A. Bresnick, F. B. Gertler, J. S. Condeelis, M. H. Oktay, Invasive breast carcinoma cells from patients exhibit MenaINV- and macrophage-dependent transendothelial migration. Sci. Signal. 7, ra112 (2014).
30
L. Chen, J. Li, F. Wang, C. Dai, F. Wu, X. Liu, T. Li, R. Glauben, Y. Zhang, G. Nie, Y. He, Z. Qin, Tie2 expression on macrophages is required for blood vessel reconstruction and tumor relapse after chemotherapy. Cancer Res. 76, 6828–6838 (2016).
31
A. Patsialou, Y. Wang, J. Lin, K. Whitney, S. Goswami, P. A. Kenny, J. S. Condeelis, Selective gene-expression profiling of migratory tumor cells in vivo predicts clinical outcome in breast cancer patients. Breast Cancer Res. 14, R139 (2012).
32
A. C. Society, Breast Cancer Facts & Figures 2015-2016 (American Cancer Society Inc., 2015).
33
T. Shree, O. C. Olson, B. T. Elie, J. C. Kester, A. L. Garfall, K. Simpson, K. M. Bell-McGuinn, E. C. Zabor, E. Brogi, J. A. Joyce, Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev. 25, 2465–2479 (2011).
34
F. Pucci, M. A. Venneri, D. Biziato, A. Nonis, D. Moi, A. Sica, C. Di Serio, L. Naldini, M. De Palmax, A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes, blood “resident” monocytes, and embryonic macrophages suggests common functions and developmental relationships. Blood 114, 901–914 (2009).
35
C. Murdoch, M. Muthana, S. B. Coffelt, C. E. Lewis, The role of myeloid cells in the promotion of tumour angiogenesis. Nat. Rev. Cancer 8, 618–631 (2008).
36
C. E. Lewis, A. S. Harney, J. W. Pollard, The multifaceted role of perivascular macrophages in tumors. Cancer Cell 30, 18–25 (2016).
37
E. Fremder, M. Munster, A. Aharon, V. Miller, S. Gingis-Velitski, T. Voloshin, D. Alishekevitz, R. Bril, S. J. Scherer, D. Loven, B. Brenner, Y. Shaked, Tumor-derived microparticles induce bone marrow-derived cell mobilization and tumor homing: A process regulated by osteopontin. Int. J. Cancer 135, 270–281 (2014).
38
C. L. Forse, S. Agarwal, D. Pinnaduwage, F. Gertler, J. S. Condeelis, J. Lin, X. Xue, K. Johung, A. M. Mulligan, T. E. Rohan, S. B. Bull, I. L. Andrulis, Menacalc, a quantitative method of metastasis assessment, as a prognostic marker for axillary node-negative breast cancer. BMC Cancer 15, 483 (2015).
39
S. Agarwal, F. B. Gertler, M. Balsamo, J. S. Condeelis, R. L. Camp, X. Xue, J. Lin, T. E. Rohan, D. L. Rimm, Quantitative assessment of invasive mena isoforms (Menacalc) as an independent prognostic marker in breast cancer. Breast Cancer Res. 14, R124 (2012).
40
M. J. Oudin, S. K. Hughes, N. Rohani, M. N. Moufarrej, J. G. Jones, J. S. Condeelis, D. A. Lauffenburger, F. B. Gertler, Characterization of the expression of the pro-metastatic MenaINV isoform during breast tumor progression. Clin. Exp. Metastasis 33, 249–261 (2016).
41
G. Bonadonna, A. Moliterni, M. Zambetti, M. G. Daidone, S. Pilotti, L. Gianni, P. Valagussa, 30 years’ follow up of randomised studies of adjuvant CMF in operable breast cancer: Cohort study. BMJ 330, 217 (2005).
42
G. Bonadonna, E. Brusamolino, P. Valagussa, A. Rossi, L. Brugnatelli, C. Brambilla, M. De Lena, G. Tancini, E. Bajetta, R. Musumeci, U. Veronesi, Combination chemotherapy as an adjuvant treatment in operable breast cancer. N. Engl. J. Med. 294, 405–410 (1976).
43
J. M. Roodhart, M. H. Langenberg, J. S. Vermaat, M. P. Lolkema, A. Baars, R. H. Giles, E. O. Witteveen, E. E. Voest, Late release of circulating endothelial cells and endothelial progenitor cells after chemotherapy predicts response and survival in cancer patients. Neoplasia 12, 87–94 (2010).
44
D. G. DeNardo, D. J. Brennan, E. Rexhepaj, B. Ruffell, S. L. Shiao, S. F. Madden, W. M. Gallagher, N. Wadhwani, S. D. Keil, S. A. Junaid, H. S. Rugo, E. S. Hwang, K. Jirström, B. L. West, L. M. Coussens, Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011).
45
C. Murdoch, S. Tazzyman, S. Webster, C. E. Lewis, Expression of Tie-2 by human monocytes and their responses to angiopoietin-2. J. Immunol. 178, 7405–7411 (2007).
46
M. A. Venneri, M. De Palma, M. Ponzoni, F. Pucci, C. Scielzo, E. Zonari, R. Mazzieri, C. Doglioni, L. Naldini, Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer. Blood 109, 5276–5285 (2007).
47
M. De Palma, L. Naldini, Angiopoietin-2 TIEs up macrophages in tumor angiogenesis. Clin. Cancer Res. 17, 5226–5232 (2011).
48
C. E. Lewis, A. S. Harney, J. W. Pollard, The multifaceted role of perivascular macrophages in tumors. Cancer Cell 30, 365 (2016).
49
M. J. Oudin, L. Barbier, C. Schäfer, T. Kosciuk, M. A. Miller, S. Han, O. Jonas, D. A. Lauffenburger, F. B. Gertler, MENA confers resistance to paclitaxel in triple-negative breast cancer. Mol. Cancer Ther. 16, 143–155 (2017).
50
S. K. Swisher, J. Vila, S. L. Tucker, I. Bedrosian, S. F. Shaitelman, J. K. Litton, B. D. Smith, A. S. Caudle, H. M. Kuerer, E. A. Mittendorf, Locoregional control according to breast cancer subtype and response to neoadjuvant chemotherapy in breast cancer patients undergoing breast-conserving therapy. Ann. Surg. Oncol. 23, 749–756 (2016).
51
F. M. Blows, K. E. Driver, M. K. Schmidt, A. Broeks, F. E. van Leeuwen, J. Wesseling, M. C. Cheang, K. Gelmon, T. O. Nielsen, C. Blomqvist, P. Heikkilä, T. Heikkinen, H. Nevanlinna, L. A. Akslen, L. R. Bégin, W. D. Foulkes, F. J. Couch, X. Wang, V. Cafourek, J. E. Olson, L. Baglietto, G. G. Giles, G. Severi, C. A. McLean, M. C. Southey, E. Rakha, A. R. Green, I. O. Ellis, M. E. Sherman, J. Lissowska, W. F. Anderson, A. Cox, S. S. Cross, M. W. R. Reed, E. Provenzano, S.-J. Dawson, A. M. Dunning, M. Humphreys, D. F. Easton, M. García-Closas, C. Caldas, P. D. Pharoah, D. Huntsman, Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: A collaborative analysis of data for 10,159 cases from 12 studies. PLOS Med. 7, e1000279 (2010).
52
L. Zhang, S. Riethdorf, G. Wu, T. Wang, K. Yang, G. Peng, J. Liu, K. Pantel, Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin. Cancer Res. 18, 5701–5710 (2012).
53
J.-Y. Pierga, F.-C. Bidard, C. Mathiot, E. Brain, S. Delaloge, S. Giachetti, P. de Cremoux, R. Salmon, A. Vincent-Salomon, M. Marty, Circulating tumor cell detection predicts early metastatic relapse after neoadjuvant chemotherapy in large operable and locally advanced breast cancer in a phase II randomized trial. Clin. Cancer Res. 14, 7004–7010 (2008).
54
W. Onstenk, J. Kraan, B. Mostert, M. M. Timmermans, A. Charehbili, V. T. H. B. M. Smit, J. R. Kroep, J. W. R. Nortier, S. van de Ven, J. B. Heijns, L. W. Kessels, H. W. M. van Laarhoven, M. M. E. M. Bos, C. J. H. van de Velde, J. W. Gratama, A. M. Sieuwerts, J. W. M. Martens, J. A. Foekens, S. Sleijfer, Improved circulating tumor cell detection by a combined EpCAM and MCAM CellSearch enrichment approach in patients with breast cancer undergoing neoadjuvant chemotherapy. Mol. Cancer Ther. 14, 821–827 (2015).
55
C. T. Guy, R. D. Cardiff, W. J. Muller, Induction of mammary tumors by expression of polyomavirus middle T oncogene: A transgenic mouse model for metastatic disease. Mol. Cell. Biol. 12, 954–961 (1992).
56
F. Ahmed, J. Wyckoff, E. Y. Lin, W. Wang, Y. Wang, L. Hennighausen, J.-i. Miyazaki, J. Jones, J. W. Pollard, J. S. Condeelis, J. E. Segall, GFP expression in the mammary gland for imaging of mammary tumor cells in transgenic mice. Cancer Res. 62, 7166–7169 (2002).
57
D. Entenberg, J. Wyckoff, B. Gligorijevic, E. T. Roussos, V. V. Verkhusha, J. W. Pollard, J. Condeelis, Setup and use of a two-laser multiphoton microscope for multichannel intravital fluorescence imaging. Nat. Protoc. 6, 1500–1520 (2011).
58
D. Entenberg, D. Kedrin, J. Wyckoff, E. Sahai, J. Condeelis, J. E. Segall, Imaging tumor cell movement in vivo. Curr. Protoc. Cell Biol. Chapter 19, Unit 19.7 (2013).
59
C. A. Schneider, W. S. Rasband, K. W. Eliceiri, NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 9, 671–675 (2012).
60
J. B. Wyckoff, J. G. Jones, J. S. Condeelis, J. E. Segall, A critical step in metastasis: In vivo analysis of intravasation at the primary tumor. Cancer Res. 60, 2504–2511 (2000).
61
P. Thevenaz, U. E. Ruttimann, M. Unser, A pyramid approach to subpixel registration based on intensity. IEEE Trans. Image Process. 7, 27–41 (1998).
62
P. J. Boimel, T. Smirnova, Z. N. Zhou, J. Wyckoff, H. Park, S. J. Coniglio, B.-Z. Qian, E. R. Stanley, D. Cox, J. W. Pollard, W. J. Muller, J. Condeelis, J. E. Segall, Contribution of CXCL12 secretion to invasion of breast cancer cells. Breast Cancer Res. 14, R23 (2012).
63
H. Gil-Henn, A. Patsialou, Y. Wang, M. S. Warren, J. S. Condeelis, A. J. Koleske, Arg/Abl2 promotes invasion and attenuates proliferation of breast cancer in vivo. Oncogene 32, 2622–2630 (2013).
64
T. D. Schmittgen, K. J. Livak, Analyzing real-time PCR data by the comparative CT method. Nat. Protoc. 3, 1101–1108 (2008).
65
M. D. Weidmann, C. R. Surve, R. J. Eddy, X. Chen, F. B. Gertler, V. P. Sharma, J. S. Condeelis, MenaINV dysregulates cortactin phosphorylation to promote invadopodium maturation. Sci. Rep. 6, 36142 (2016).
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Science Translational Medicine
Volume 9 • Issue 397 • 5 July 2017
History
Received: 20 February 2017
Accepted: 13 June 2017
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Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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http://dx.doi.org/10.13039/100000052NIH Office of the Director: award312450, CA100324
http://dx.doi.org/10.13039/100000052NIH Office of the Director: award312451, CA150344
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Integrated Imaging Program: award312455, N/A
Comment on "The Neoadjuvant chemotherapy (NAC) setting provides an opportunity to study mechanisms of resistance to therapy but should not be portrayed as inducing clinical breast cancer metastasis"
The findings reported by Karaglannis et al. (1) demonstrate a potentially important advance in our understanding of how metastases occur in some tumor types. However, the data presented are far from sufficient to justify the conclusion that neoadjuvant chemotherapy causes metastases in breast cancer patients (2).
The mouse data demonstrate a mechanism whereby taxane-resistant cancer can escape and metastasize. Transgenic aggressive murine models were used and the responses obtained to paclitaxel were partial at best - a control group of mouse tumors highly responsive to taxanes that illuminated TMEM function in responsive tumors would be required to conclude that taxanes induce metastases in all tumors. Furthermore, the duration of treatment regimens used were not comparable to typical clinical neoadjuvant taxanes protocols.
Evidence that this mechanism is clinically active comes from only a limited number of cases (7 from one series and 5 from another), all of which had residual tumor following neoadjuvant chemotherapy. Residual disease at time of surgery is a well established predictor of poor outcome (metastasis), which over multiple trials and meta-analyses has clearly been shown to be associated with an increased risk of metastatic disease. Cases where pathologic complete response (pCR) was achieved were not evaluated in this manuscript, however, 13-50% of high-risk breast cancers achieve a pCR following taxane-based chemotherapy. Patients who achieve complete pathologic response have consistently better long-term outcomes and event-free recurrence (3).
A number of trials have demonstrated that taxanes improve distant metastasis disease free survival, especially in more aggressive tumor types (4, 5). Multiple large trials have also clearly established that order of therapy does not impact survival (6, 7), including NSABP B-27 where paclitaxel was given after doxorubicin either before or after primary surgery. NSABP B-28, a randomized trial of 3060 women, showed that paclitaxel, when added to doxorubicin and cyclophosphamide, decreased the chance of metastatic disease by 17%. NSABP B-27 showed that whether paxlitaxel is given before or after surgical resection, the chance of metastasis is the same. Many trials have shown that the order of therapy does not impact survival t, which has allowed the neoadjuvant setting to be a driver for drug development and improve surgical and radiation adjuvant options. The cornerstone of modern advances in NAC has been that patients who achieve complete pathologic response to chemotherapy have consistently better long-term outcomes and disease-free recurrence.This, in fact, is one of the primary reasons the neoadjuvant treatment has become an important driver for drug development while also improving surgical and radiation adjuvant treatment options (8-10).
Given that that this study evaluated only those with residual disease, a more appropriate and actionable conclusion is that the authors have delineated a potential mutable mechanism of resistance to chemotherapy. This finding becomes more significant with the existence of a class of drugs that targets this pathway. The TIE2 inhibitor, AMG 386, when added to standard therapy in the I-SPY2 trial, improved the chance of pCR in the most proliverative tumors (11). Indeed, this is an exciting avenue for further investigation and combinations that include agents that block the tumor microenvironment of metastases should be evaluated and are being investigated as potential agents for the I-SPY2 TRIAL.
However, provocative statements that imply that chemotherapy induces metastases are misleading and frightening to patients. Numerous headlines spawned by this manuscript led some patients to believe that NAC could increase their chance of death, thereby causing women to avoid treatments that are potentially curative and part of the standard of care. There are a number of important neoadjuvant clinical trials focused on developing more effective treatments; one recent combination in the I-SPY2 TRIAL tripled the chance of pCR. We certainly do not want to inappropriately discourage women from participating in trials that explore possible options to improve pCR and have led to numerous opportunities to change the standard of care. We are certain that the authors did not intend to send this message.
Signed,
Laura Esserman
Andres Forero
Hope Rugo
Anna Barker
Angie DeMichele
Jane Perlmutter
Christina Yau
Denise Wolf
Kathy Albain
Michael Alvarado
Doug Yee
References
1. G. S. Karagiannis, J. M. Pastoriza, Y. Wang, A. S. Harney, D. Entenberg, J. Pignatelli, V. P. Sharma, E. A. Xue, E. Cheng, T. M. D'Alfonso, J. G. Jones, J. Anampa, T. E. Rohan, J. A. Sparano, J. S. Condeelis, M. H. Oktay, Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism, Sci Transl Med 9, eaan0026 (2017).
2. A. DeMichele, D. Yee, L. Esserman, E. G. Phimister, Ed. Mechanisms of Resistance to Neoadjuvant Chemotherapy in Breast Cancer, http://dx.doi.org/10.1056/NEJMcibr1711545 377, 2287–2289 (2017).
3. S. S. Mougalian, M. Hernandez, X. Lei, S. Lynch, H. M. Kuerer, W. F. Symmans, R. L. Theriault, B. D. Fornage, L. Hsu, T. A. Buchholz, A. A. Sahin, K. K. Hunt, W. T. Yang, G. N. Hortobagyi, V. Valero, Ten-Year Outcomes of Patients With Breast Cancer With Cytologically Confirmed Axillary Lymph Node Metastases and Pathologic Complete Response After Primary Systemic Chemotherapy, JAMA Oncol 2, 508–516 (2016).
4. E. P. Mamounas, J. Bryant, B. Lembersky, L. Fehrenbacher, S. M. Sedlacek, B. Fisher, D. L. Wickerham, G. Yothers, A. Soran, N. Wolmark, Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28, Journal of Clinical Oncology 23, 3686–3696 (2005).
5. J. L. Blum, P. J. Flynn, G. Yothers, L. Asmar, C. E. GeyerJr, S. A. Jacobs, N. J. Robert, J. O. Hopkins, J. A. O'Shaughnessy, C. T. Dang, H. L. Gómez, L. Fehrenbacher, S. J. Vukelja, A. P. Lyss, D. Paul, A. M. Brufsky, J.-H. Jeong, L. H. Colangelo, S. M. Swain, E. P. Mamounas, S. E. Jones, N. Wolmark, Anthracyclines in Early Breast Cancer: The ABC Trials—USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology), Journal of Clinical Oncology, JCO.2016.71.414 (2017).
6. D. Mauri, N. Pavlidis, J. P. A. Ioannidis, Neoadjuvant Versus Adjuvant Systemic Treatment in Breast Cancer: A Meta-Analysis, JNCI 97, 188–194 (2005).
7. P. Rastogi, S. J. Anderson, H. D. Bear, C. E. Geyer, M. S. Kahlenberg, A. Robidoux, R. G. Margolese, J. L. Hoehn, V. G. Vogel, S. R. Dakhil, D. Tamkus, K. M. King, E. R. Pajon, M. J. Wright, J. Robert, S. Paik, E. P. Mamounas, N. Wolmark, Preoperative Chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27, Journal of Clinical Oncology 26, 778–785 (2008).
8. J. W. Park, M. C. Liu, D. Yee, C. Yau, L. J. van t Veer, W. F. Symmans, M. Paoloni, J. Perlmutter, N. M. Hylton, M. Hogarth, A. DeMichele, M. B. Buxton, A. J. Chien, A. M. Wallace, J. C. Boughey, T. C. Haddad, S. Y. Chui, K. A. Kemmer, H. G. Kaplan, C. Isaacs, R. Nanda, D. Tripathy, K. S. Albain, K. K. Edmiston, A. D. Elias, D. W. Northfelt, L. Pusztai, S. L. Moulder, J. E. Lang, R. K. Viscusi, D. M. Euhus, B. B. Haley, Q. J. Khan, W. C. Wood, M. Melisko, R. Schwab, T. Helsten, J. Lyandres, S. E. Davis, G. L. Hirst, A. Sanil, L. J. Esserman, D. A. Berry, Adaptive Randomization of Neratinib in Early Breast Cancer, N Engl J Med 375, 11–22 (2016).
9. H. S. Rugo, O. I. Olopade, A. DeMichele, C. Yau, L. J. van t Veer, M. B. Buxton, M. Hogarth, N. M. Hylton, M. Paoloni, J. Perlmutter, W. F. Symmans, D. Yee, A. J. Chien, A. M. Wallace, H. G. Kaplan, J. C. Boughey, T. C. Haddad, K. S. Albain, M. C. Liu, C. Isaacs, Q. J. Khan, J. E. Lang, R. K. Viscusi, L. Pusztai, S. L. Moulder, S. Y. Chui, K. A. Kemmer, A. D. Elias, K. K. Edmiston, D. M. Euhus, B. B. Haley, R. Nanda, D. W. Northfelt, D. Tripathy, W. C. Wood, C. Ewing, R. Schwab, J. Lyandres, S. E. Davis, G. L. Hirst, A. Sanil, D. A. Berry, L. J. Esserman, Adaptive Randomization of Veliparib–Carboplatin Treatment in Breast Cancer, N Engl J Med 375, 23–34 (2016).
10. J. Baselga, I. Bradbury, H. Eidtmann, S. Di Cosimo, E. de Azambuja, C. Aura, H. Gómez, P. Dinh, K. Fauria, V. Van Dooren, G. Aktan, A. Goldhirsch, T.-W. Chang, Z. Horváth, M. Coccia-Portugal, J. Domont, L.-M. Tseng, G. Kunz, J. H. Sohn, V. Semiglazov, G. Lerzo, M. Palacova, V. Probachai, L. Pusztai, M. Untch, R. D. Gelber, M. Piccart-Gebhart, Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial, The Lancet 379, 633–640 (2012).
11. K. S. Albain, B. Leyland-Jones, F. Symmans, M. Paolini, L. J. van't Veer, A. DeMichele, M. Buxton, N. M. Hylton, D. Yee, J. Lyandres, C. Yau, A. Sanil, I-SPY2 Trial Investigators, D. Berry, L. J. Esserman, The evaluation of trebananib plus standard neoadjuvant therapy in high-risk breast cancer: Results from the I-SPY2 Trial. San Antonio Breast Cancer Symposium (2016).