Estrogen Receptor–Negative Breast Cancer: New Insights Into Subclassification and Targeting □□ Commentary on Speers Et Al., P

Published OnlineFirst October 13, 2009; DOI: 10.1158/1078-0432.CCR-09-2010 Published Online First on October 13, 2009 as 10.1158/1078-0432.CCR-09-2010 CCR Translations

Estrogen Receptor–Negative Breast Cancer: New Insights into Subclassification and Targeting □□ Commentary on Speers et al., p. 6327

Jean J. Zhao1,2 and Daniel P. Silver3,4

Classification schemes for disease states can help identify distinctions with useful implications for therapy and prognosis. Speers and colleagues provide a new subclassification scheme for estrogen receptor-negative breast cancer based upon kinome-wide gene expression profiling with interesting findings that are potentially relevant for both treatment and clinical outcome. (Clin Cancer Res 2009;15(20):6309–10)

In this issue of Clinical Cancer Research, Speers and colleagues chemotherapysensitive, and even if we did have such tools, (1) provide new insight into estrogen receptor (ER)-negative there is no established therapyto offer to those patients who breast cancer. Breast cancer is not one disease, but many. Phy- are not chemotherapysensitive. sicians have long realized that some breast cancers are respon- Speers and colleagues (1) make interesting contributions to sive to hormonal manipulation; we now know that these both the classification issue and the therapyissue. The authors cancers express the estrogen and/or progesterone receptors. In use transcriptional microarraydata to look for kinases that were addition, in the mid-1980s, it became clear that about 25% differentiallyexpressed in ER-positive compared with ER-negative of breast cancer overexpresses the Her2/Neu receptor tyrosine breast tumors. Of 779 known or putative human kinases and kinase as a result of a specific genomic amplification event kinase-interacting proteins, 86 were differentiallyexpressed in (2). Analysis of gene expression microarray data recapitulated these two sets of breast cancers at the P < 0.05 level. 52 of these these clinical categories, and added two nuances. ER-positive 86 genes were expressed at a level at least twofold higher than Her2/Neu nonamplified breast cancers could be subdivided in the ER-negative breast cancer group and were chosen for further bytheir pattern of gene expression into two groups, the relative- study. The authors then used the expression of these 52 kinases to lyindolent luminal A tumors, and the more aggressive luminal subclassifyER-negative tumors and cell lines; this produced four B tumors. Furthermore, transcriptional arrayprofiling showed distinct subtypes of ER-negative breast cancer, designated by the that, at least at first glance, the breast cancers that do not express authors as the map kinase cluster, the immunomodulatorycluster, hormone receptors or harbor Her2/Neu amplification, the so- the S6 kinase cluster, and the cell cycle checkpoint cluster, on the called basal-like or triple negative breast cancers, seem to be a basis of the kinases highlyexpressed within each group. ER- relativelyhomogeneous group (3). negative cell lines also fell into the same four groups. Because The classification of breast cancers in this manner is not an the authors chose to focus on ER-negative breast cancer with- idle academic pursuit; significant therapeutic implications are out regard to Her2/Neu amplification, ER-negative Her2/Neu conveyed by these distinctions. Hormonal therapy targeting amplified tumors were included in this study. Most of these the ER signal transduction pathwayis a mainstayof the treat- tumors fell within the immune group. The map kinase group ment of ER-positive tumors. Her2/Neu amplified tumors can be consisted almost entirelyof luminal B tumors or Her2/Neu treated with therapytargeting the Her2/Neu molecule, and the amplified tumors; the reasons for the presence of luminal B humanized monoclonal antibodytrastuzumab has made a sig- tumors among ER-negative breast cancers in this studyare un- nificant impact on the treatment of this subtype of breast cancer clear (the vast majorityare ER positive), but mayrelate to the – (4 6). At the present time, patients with triple negative tumors thresholds used to determine ER negativityin this study.The do not have the benefit of targeted therapy(see Fig. 1). We S6 kinase group and the cell cycle checkpoint group seemed to know that a fraction of triple negative tumors are responsive subdivide the triple negative tumors into two distinct groups. to standard chemotherapies (7, 8); however, at the moment What potential clinical utilitymight offer this subdivision of we lack tools to predict which triple negative tumors will be ER-negative breast tumors? Speers and colleagues show that metastasis-free survival and overall survival differ among tu-

1 mors divided into the groups defined above. Moreover, they Authors' Affiliations: Department of Cancer Biology, Dana-Farber Cancer EPHB4, LIMK2, DAPK1, Institute; 2Department of Pathology, Harvard Medical School; 3Department of suggest that some of these kinases, e.g., Medical Oncology, Dana-Farber Cancer Institute; and 4Department of Medicine, YES1, RYK, VRK2, PTK7, which are differentiallyexpressed in Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts ER-negative breast cancer, mayserve as “druggable targets” for Received 8/19/09; accepted 8/20/09; published OnlineFirst 10/13/09. the treatment of ER-negative breast cancer, and in particular, for Requests for reprints: Daniel P. Silver, 1 Jimmy Fund Way, Boston, MA 02115. Phone: 617-582-8485; Fax: 617-632-4381; E-mail: [email protected]. the treatment of basal-like triple negative breast cancer. F 2009 American Association for Cancer Research. Kinases are keyregulators of signaling pathwaysthat control doi:10.1158/1078-0432.CCR-09-2010 manycellular functions including proliferation, migration,

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CCR Translations

Fig. 1. The relationship of breast cancer clinical classification (top line), targeted therapies available, and the kinase-based subclassification of Speers et al.

and survival. Perturbation of kinase signaling bymutations, underlying and accompanying increased expression of these genomic amplification, or other genetic alterations is a frequent kinases in ER-negative breast cancer? Does elevated expression event central to tumorigenesis in manycancers. Fortunately,ki- of these kinases actuallyrender the tumors more sensitive to the nases have proven to be good druggable targets. For example, relevant inhibitors? The authors show that siRNA-mediated in- imatinib (also called Gleevec or STI571, Novartis) is the first hibition of various kinases inhibit growth in cell culture; a crit- FDA-approved drug of this new class of agents that directly ical issue for the future will be to see if small molecule kinase block the signal of a kinase; Imatinib significantlybenefits pa- inhibitors that can be developed into drugs also have similar tients with chronic myelogenous leukemia (CML) featuring effect. To date, most kinase inhibitors have shown maximal BCR-ABL fusions, and also patients with gastrointestinal stro- clinical benefit in tumors in which the gene encoding the rele- mal tumor (GIST). Since then, the development of molecularly vant kinase is either amplified, translocated, or harbors a gain- targeted drugs that inhibit the action or activityof oncogenic of-function mutation. Whether anyof these changes are present kinases or their signaling pathways has been one of the most in anyof these kinases in ER-negative breast cancer is largely exciting and productive areas in cancer therapy. Gefitinib (Ires- unknown. Recent studies have revealed that a high percentage sa, AstraZeneca) and erlotinib (Tarceva, Genentech/OSI/Roche) of triple negative breast cancer have lost the tumor suppressor have been developed for the treatment of patients with lung phosphatase and tensin homolog (PTEN; ref. 9). Loss of PTEN cancer bearing mutations and/or amplification of the epidermal is perhaps the most common mechanism of activation of the growth factor receptor (EGFR) tyrosine kinase. Trastuzumab phosphoinositide 3-kinase (PI3K) pathway. Notably, the im- (Herceptin, Genentech/Roche) and lapatinib (Tykerb, GlaxoS- portance of one of the PI3K isoforms, PIK3CB as a “driver” mithKline) have proven to be effective treatments for patients for cancer cell growth in the absence of PTEN has been recently with Her2 positive breast cancer. Unfortunately, the 20% of shown (10, 11), making PI3KCB a promising target in PTEN- breast cancer patients who suffer from triple negative breast null tumors. Intriguingly, PIK3CB is also one of the kinases cancer lacking expression of ER and Her2 do not have the ad- identified bySpeers and colleagues to be highlyexpressed in vantage of benefiting from modern targeted therapies, and thus triple negative breast cancer. It would be worthwhile to explore identification of a “druggable” target could have tremendous the correlation between PTEN loss and high expression of clinical impact on triple negative breast cancer therapy. PIK3CB in triple negative breast cancer. Elucidation of the roles Interestingly, the current study finds that a number of the ki- of these and manyother kinase signaling pathwaysin triple nases that are highlyexpressed in ER-negative breast cancer also negative breast cancer should provide important insights into seem to be important for the growth of triple negative breast molecular mechanisms of signaling action and help identify cancer cells (MDA-MB-468 and MDA-MB-231) but not for prime candidates for therapeutic intervention. ER-positive breast cancer cells (MCF7 and T47D) in culture. However, this finding is onlyan earlystep toward targeted drug Disclosure of Potential Conflicts of Interest discovery, and many questions remain to be answered. For example, what are the mechanisms and biological consequences J.J. Zhao, consultant, Novartis Pharmaceuticals.

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Estrogen Receptor−Negative Breast Cancer: New Insights into Subclassification and Targeting

Jean J. Zhao and Daniel P. Silver

Clin Cancer Res Published OnlineFirst October 13, 2009.

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