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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003ETechnological breakthroughs have enabled researchers to obtain more detailed information regarding the genetic composition of tumors in breast cancer. Cancerous tumors are incredibly diverse, single resistant cells may mutate and metastasize, and new therapies will have to attack the tumor support systems on multiple fronts to eliminate malignancies.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Etreatment outlook\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Emetastatic disease\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Emetastasis\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Egenetic analysis\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EWhile the current outlook for most patients with breast cancer (BC) is positive, challenges remain in finding the optimal therapies for the patients diagnosed with metastatic disease, according to Joan S. Brugge, PhD, Harvard Medical School, Boston, Massachusetts, USA, who shared her thoughts on the future treatment of these patients.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EAdvances in the genetic analysis of tumors have revealed astounding genetic diversity in BC. Multiple alterations are possible, with each patient having individual patterns of alterations. Questions that have emerged include how current therapies are affected by these variable alterations and whether therapies will need to be based on the genetic patterns of each patient. For example, research has shown that human epidermal growth factor receptor 2 (HER2)\u2013targeted therapies are less effective in patients with amplified HER2 and PIK3CA alterations; adding a PIK3CA inhibitor may increase the effectiveness of HER2 therapies in patients with these combined alterations. Dr Brugge said that not all of the alterations influence sensitivity to therapy, and clinicians may be able to stratify patients into a still large but manageable number of subsets, which can be treated with different combinations.\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EWithin each tumor, there may also be significant heterogeneity. Within a tumor, cells that are sensitive to a particular agent will be killed, leaving the surviving resistant cells. This can lead to variable success in the treatment of each tumor within a patient. Recent evidence suggests that a single residual cell can develop into a recurrent tumor. A patient with metastatic BC did not respond to standard chemotherapy and was found to have an activating PIK3CA mutation [Juric D et al. \u003Cem\u003ENature\u003C\/em\u003E. 2014]. The patient was treated with the PIK3CA-specific inhibitor BYL719 in a clinical trial. After an initial response, the patient developed resistance to the drug and died. Genetic sequencing of metastatic sites showed additional and different PTEN genetic alterations in nonresponding tumors. The fact that these alterations were not present in the primary tumor suggests that a single cell mutated and was able to expand to produce a recurrent tumor in the presence of a drug. Dr Brugge noted the implication that every cell in a tumor must be deleted to prevent regression, which would present a serious treatment challenge.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EThe most effective tactics of the future will be those that disrupt the tumor ecosystem and block the ability of tumor cells to adapt. This will be a complicated approach requiring multiple agents. One potential strategy is to find the critical nodes of interaction within the tumor ecosystem and target them simultaneously to prevent adaptation. For example, the combination of hormone therapy, a stem cell\u2013targeted inhibitor, a macrophage inhibitor, and a checkpoint inhibitor might prove to be effective. Taking out these nodes would cut off the support system of tumor cells, making them more vulnerable to destruction by the immune system. Another option is to target programs that are \u201cdownstream\u201d from oncogenic pathways and pathways activated by microenvironment factors that coalesce to regulate cell survival in the context of cancer therapy, thus preventing \u201cadaptation.\u201d\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 SAGE Publications\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/56\/15.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzo852\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}