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that predictive biomarkers accompany targeted drugs, we can follow thestellar example of HER2- and HR-directed agents, enhancing efficacy andensuring that only those patients likely to respond are exposed to toxic-ities. We can make sure that treatments offered truly make a difference inpeoples’ lives, and extend survival.The increase inmedian survival in thepast decadeor so formanyHER2+ andHR+ metastatic breast cancer patients has been driven primarily by theintroduction of Herceptin and the aromatase inhibitors. Survival has notchanged for patients with drug resistant or triple-negative disease.xv Thefrequent use of the term “chronic” to describe metastatic breast cancer hasthus become a sore point for many of these patients, who feel it trivializesthe deadly progressive nature of their illness, and maintains an illusion ofprogress that is still far from reality. But if we can turn the term “chronic”into a reality for them, it will be cause for celebration.Finally, if the confusion patients face in making treatment decisions can bereduced, and if meaningful guidelines can be crafted that account forindividual differences, respecting patient preferences, it will help womenand men with metastatic breast cancer to manage the anxiety and loss ofconfidence they feel when each treatment fails, as it inevitably does. It willhelp them to make sense of divergent second opinions.So, the challenges are clear. The opportunities are many. The 2011 ABC1Consensus Conference in Lisbon is a crucial and hopeful first step. Patientsand advocates all over the world are watching and ready to partner withyou, grateful that our time has come, at last.Listed below

i WorldHealthOrganization. Summary: Projected deaths (000s) by cause,in WHO regions (a), baseline scenario 2008. (Accessed July 13, 2011)http://who.int/healthinfo/global_burden_disease/Dth6_2008.xls

ii O'Shaughnessy J. Extending survival with chemotherapy in metastaticbreast cancer. Oncologist 2005;10:20-29. (Accessed July 17, 2011)http://theoncologist.alphamedpress.org/content/10/suppl_3/20.full.pdf+html

iii Parkin DM, Bray F, Ferlay J, Pisani P. Global Cancer Statistics, 2002. CACancer J Clin 2005;55:74–108. (Accessed July 17, 2011) http://caonline.amcancersoc.org/cgi/reprint/55/2/74

iv Chia SK, Speers CH, D'yachkova Y, et al. The impact of new chemo-therapeutic and hormone agents on survival in a population-basedcohort of womenwith metastatic breast cancer. Cancer 2007;110:973–979. (Accessed July 17, 2011) http://onlinelibrary.wiley.com/doi/10.1002/cncr.22867/pdf

v Giordano SH, Buzdar Au, Smith Tl, et al. Is breast cancer survivalimproving? Cancer 2004; 100(1): 44-52. (Accessed July 17, 2011)http://onlinelibrary.wiley.com/doi/10.1002/cncr.11859/pdf

vi See, for example, the Metastatic Breast Cancer Network at www.mbcnetwork.org and METAvivor at www.metavivor.org

vii MayerM, Grober S. Silent voices: womenwithmetastatic breast cancershare their needs and preferences for information, support and prac-tical services. Living Beyond Breast Cancer, 2006. (Accessed July 13,2011) http://www.lbbc.org/Understanding-Breast-Cancer/Guides-to-Understanding-Breast-Cancer/Silent-Voices

viii Mayer, M. Lessons Learned from the Metastatic Breast Cancer Commu-nity, Seminars in Oncology Nursing, Vol 26, No 3 (August), 2010: pp195-202. (Accessed July 13, 2011) http://mbcnetwork.org/images/uploads/MayerLessonsLearned-2.pdf

ix MayerM, Hunis A, Oratz, R, Glennon C, Spicer P, Caplan E, FallowfieldL. Living with metastatic breast cancer: a global patient survey. Com-minityOncology, September 2010, p. 406-12. (Accessed July 13, 2011)http://www.communityoncology.net/journal/articles/0709406.pdf

x BCMets.org Metastatic Breast Cancer Information and Support,archives and mailing list (Accessed July 13, 2011) http://bcmets.org/

xi World Health Organization, Cancer Fact Sheet, February 2011.(Accessed July 17, 2011) http://www.who.int/mediacentre/factsheets/fs297/en/

xii Steeg, PS, Theodoescu, D, Metastasis: a therapeutic target for cancer.Nat Clin Pract Oncol. 2008 April ; 5(4): 206–219. (Accessed July 17,2011) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2709494/

xiii Sleeman, J, Steeg, PS. Cancer metastasis as a therapeutic target,European Journal of Cancer, 46 (2010) 1177 –1180. (Accessed July 17,

2011) http://www.ecco-org.eu/binarydata.aspx?type¼doc/Cancer_metastasis_as_a_therapeutic_target.pdf

xiv Leaf, C Why We're Losing the War on Cancer [and how to win it],Fortune Magazine, March 22, 2004. (Accessed July 17, 2011) http://money.cnn.com/magazines/fortune/fortune_archive/2004/03/22/365076/

xv Shigematsu H, Kawaguchi H, Nakamura Y, et al. Significant survivalimprovement of patients with recurrent breast cancer in the periods2001-2008 vs. 1992-2000. BMC Cancer. 2011 Mar 31;11:118.(Accessed July 17, 2011) http://www.biomedcentral.com/content/pdf/1471-2407-11-118.pdf

IN2

METASTASIS SEED PRE-SELECTION DRIVEN BY THE MICROENVIRON-MENT OF PRIMARY TUMORS

Xiang ZhangLester and Sue Smith Breast Center, Baylor College of Medicine, Houston, USA

Upon arrival at a distant organ, the disseminated breast cancer cellsencounter a new microenvironment that they have to be co-opted tosurvive. In the bone or bone marrow, Src plays an important role inmediating the survival response of cancer cells to stromal derived CXCL12and IGF1, and is critical for bonemetastasis formation. The enhancement ofSrc signalling already occurs in some primary tumors, and is prognostic ofbone relapses. It is therefore interesting to know why and how Src activityis augmented even before cancer cells reach the bone. Bioinformaticanalyses in human microarray datasets revealed that primary tumorsenriched with CXCL12 and IGF1 tend to have stronger Src signaling andworse prognosis of bone metastasis. Remarkably, as mentioned above,these same cytokines are also over-expressed in bone metastases, repre-senting a resemblance between the microenvironment of Src+ primarytumors and that of bone metastases. Experimentally, long-term incubationof breast cancer cells with purified CXCL12 and IGF1 led to the expansion ofpre-existing Src-high sub-populations and enhanced bone meta-stagenicity. We further suggested that carcinoma associated fibroblasts(CAFs) might be the source of CXCL12 and IGF1 in tumor tissues. One of thepossible origins of CAFs is mesenchymal stem cells (MSCs) from the bonemarrow. Co-injection of MSCs in mammary fat pad resulted in mammarytumors with enriched Src activity and increased bone metastasis poten-tials. These results together suggested a model of “seed pre-selection”:when the microenvironment of a primary tumor resembles that ofa distant site, it selects for cancer cells that would do better should theyarrive at that site, and therefore predisposes the tumor for site-specificmetastasis.

IN3

TISSUE-SPECIFIC METASTASES

Milica Pavlovic, Anna Arnal, Maria Tarragona, Monica Morales,Roger R. GomisInstitute for Research in Biomedicine, Growth Control and Cancer MetastasisProgramme, Barcelona, Spain

Breast cancer is the most frequently diagnosed cancer in women inEurope and the United States, with an estimated 608,380 new cases ofinvasive disease in 2007 1,2. The majority of these patients died due to thetumor metastatic spread. Our current understanding of the biology ofbreast cancer is a major barrier to identify novel therapies and improveexisting therapies for the treatment and prevention of this disease. Breastcancer is a remarkably heterogeneous disease, but subsets of tumorsshow recurrent patterns of transcriptional, genomic, and biologicalabnormality. Understanding how genes in these “patterns” collectivelyfunction in an otherwise heterogeneous biological setting to enableprogression and modulate response to therapy is critical to improve

Abstracts / The Breast 20 (2011) S12–S55S14

management of the disease. In particular, we are interested in under-standing how ER pathway contributes in leading molecular events inbreast cancer metastasis.The predisposition of primary tumors to selectively invade differentorgans has been long recognized 3. Recent work has functionallyidentified and clinically validated sets of genes whose overexpressionin ER-negative breast cancer and prostate cells confers a selectiveadvantage for the colonization of bones4,5 or lungs6. The ability tosubsequently colonize distant organs depends on the organ-colonizingfaculties of disseminated tumor cells as well as on certain requirementsthat may be present in the otherwise restrictive microenvironment oftarget organs7.Our work focuses on breast cancer metastatic suppressor genes and theirfunctions in themetastatic process. For this, we are using breast cancer cellline model and their derivatives, which have a strong metastatic capacityto lung and bone. We used these subpopulations to functionally validatea particular metastasis suppressor whose loss of expression in ER- breastcancer cells confers a selective advantage for the colonization of lung.Tumor cells under certain conditions cannot grow or survive in theabsence of a supportivemicroenvironment. Indeed, the microenvironmentmay even drive tumor and metastasis development by selecting for highlyinvasive and resistant cancer cell phenotypes and systemically fosteringthe mobilization of marrow-derived progenitor cell. In particular, loss ofexpression of our gene of interest is selected in the primary tumor. Inter-estingly, how these particular gene controls the ability to subsequentlycolonize distant organs depends on the organ-colonizing faculties ofdisseminated tumor cells rather than interaction with the restrictivemicroenvironment of target organs. Collectively, these results show thatgenes selected for metastasis contribute to the different steps and repre-sent the random accumulation of traits that provide the necessaryadvantage for adaptation to a different organ microenvironment and needat any time.1. American_Cancer_Society. Cancer facts and figures. American CancerSociety (2007).2. Ferlay, J., et al. Estimates of the cancer incidence and mortality in Europein 2006. Ann Oncol 18, 581-592 (2007).3. Paget, S. The dstribuition of secondary growths in cancer of the breast.Lancet 1, 571-573 (1889).4. Kang, Y., et al. A multigenic program mediating breast cancer metastasisto bone. Cancer Cell 3, 537-549 (2003).5. Lynch, C.C., et al. MMP-7 promotes prostate cancer-induced osteolysisvia the solubilization of RANKL. Cancer Cell 7, 485-496 (2005).6. Minn, A.J., et al. Genes that mediate breast cancer metastasis to lung.Nature 436, 518-524 (2005).7. Gupta, G.P. & Massague, J. Cancer metastasis: building a framework. Cell127, 679-695 (2006).

IN4

GENOMIC SIGNATURES OF SPECIFIC SITES OF METASTASIS

Laura van ‘t VeerUniversity of California San Francisco, USA

The conventional approach to cancer therapy, to treat according to theorgan or tissue of origin and patients’ demographics, is gradually beingreplaced by a more personalized approach in which treatment choice isbased on detailed knowledge of the genetic defects that underlie theoncogenic process in each individual tumor. As a result, we havewitnessedthe beginning of a shift from broadly-acting cytotoxic drugs towards morespecific and less toxic targeted therapies. At the same time, the annotationof the human genome has enabled the development of a new class of geneexpression-based molecular diagnostics that help to guide the choice oftherapy.The oncogenic process from primary site to metastasis requires addi-tional genetic defects, though also the genetic hard-wiring of thetumor is maintained at the distant site. Increasingly, gene expressionsignatures and single gene alterations have been identified that arespecific for outgrowth as metastasis. Tools developed for clinical

practice to assess the genetic alterations of metastasis are becomingavailable and allow us to provide personalized medicine also formetastatic patients. Such molecular diagnostics increasingly impactspatient management.

IN5

CANCER AS A DISEASE OF SELF-SEEDING

Larry NortonMemorial Sloan-Kettering Cancer Center, Breast Cancer Medicine Center,New York, USA

Epithelial cancers including breast adenocarcinomas are well charac-terized clinically, but as such present a number of enigmas that are notresolvable by conventional, unidirectional models of metastatic spread.These include phenotypic consistency of diverse features (hyperplasia,anaplasia, angiogenesis, growth rapidity with paradoxically low S-phasefraction etc.), the impact of regional radiation therapy on the control ofdisease outside of the radiation field, and the imperfect correlationbetween axillary node involvement and the probability of the develop-ment of stage IV disease. These mysteries could possibly be explained bya multidimensional model of metastases in which the primary site isboth a source and recipient of circulating cancer cells. This hypothesishas been confirmed in a variety of experimental models. Furthermore,the biological mechanisms–largely involving inflammatory cytokines,marrow-derived endothelial precursors, and infiltrating myeloid cells–are being elucidated. This approach is uncovering new molecules ofprognostic/predictive importance as well as new targets for possibletherapeutic intervention. In addition, the geometric growth patterns ofprimary tumors as discerned by MRI may have prognostic implications.Based on supportive pre-clinical experiments novel therapies thatattempt to convert primary tumors into "poisoned sponges" are inprogress.

IN6

TARGETING THE IL-6/JAK PATHWAY IN BREAST CANCER

Qing Chang 1, Pasquale Sansone 1, Min Zhang 1, Eirini Bournazou 1, RosarioAndre 2, Hector Peinado 2, Mary Alpaugh 1, Robert Schneider 4, CongYan 3, David Lyden 2, Jacqueline Bromberg 1

1Memorial Sloan Kettering Cancer Center, New York, NY, USA2Weill Medical College of Cornell University, New York, NY, USA3 Indiana University, Indianapolis, IN, USA4New York University, New York, NY, USA

Persistent activation of the IL-6/Jak/Stat3 pathway is a common feature ofmany solid tumors including breast cancer. The highest levels of IL-6 andactivated Stat3 are found on the edge of tumors primarily in fibroblasts,immune cells, endothelial and lymphatic vessels. Furthermore, paracrineIL-6 promotes autocrine IL-6 expression and signaling. We have examinedthe consequences of targeting this signaling pathway in transgenic andxenograft models of breast cancer.We have determined that mice deficientin IL-6 develop mammary tumors but these do not metastasize to the lungwhich correlates with a decrease in the recruitment of myeloid cellsincluding cd11b/gr1+ cells. Conversely, constitutive activation of Stat3 inthe bone marrow promotes expansion of cd11b/gr1+ cells. These datasuggest a role in the IL-6/Stat3 pathway in recruiting myeloid cells tometastatic sites of disease.We have also examined the role of Jak inhibitionin xenograft and transgenic models of breast cancer (e.g.Triple NegativeBreast Cancer, Inflammatory Breast Cancer) and observe a markedreduction in primary tumor growth as well as metastatic progression. Thiswas associated primarily with a reduction in angiogenesis and in therecruitment of myeloid cells to the primary tumor and to metastatic sites.In sum, these data suggest a therapeutic role in targeting the IL-6/Jak/Stat3pathway in the treatment of breast cancer by targeting both tumorintrinsic and extrinsic pathways.