Breast Cancer Metastasis

Despite important progress in adjuvant and neoadjuvant therapies, metastatic disease often develops in breast cancer patients and remains the leading cause of their deaths. For patients with established metastatic disease, therapy is palliative, with few breaks and with mounting adverse effects. Many have hypothesized that a personalized or precision approach (the terms are used interchangeably) to cancer therapy, in which treatment is based on the individual characteristics of each patient, will provide better outcomes. Here, we discuss the molecular basis of breast cancer metastasis and the challenges in personalization of treatment. The instability of metastatic tumors remains a leading obstacle to personalization, because information from a patient's primary tumor may not accurately reflect the metastasis, and one metastasis may vary from another. Furthermore, the variable presence of tumor subpopulations, such as stem cells and dormant cells, may increase the complexity of the targeted treatments needed. Although molecular signatures and circulating biomarkers have been identified in breast cancer, there is lack of validated predictive molecular markers to optimize treatment choices for either prevention or treatment of metastatic disease. Finally, to maximize the information that can be obtained, increased attention to clinical trial design in the metastasis preventive setting is needed. Despite important progress in adjuvant and neoadjuvant therapies, metastatic disease often develops in breast cancer patients and remains the leading cause of their deaths. For patients with established metastatic disease, therapy is palliative, with few breaks and with mounting adverse effects. Many have hypothesized that a personalized or precision approach (the terms are used interchangeably) to cancer therapy, in which treatment is based on the individual characteristics of each patient, will provide better outcomes. Here, we discuss the molecular basis of breast cancer metastasis and the challenges in personalization of treatment. The instability of metastatic tumors remains a leading obstacle to personalization, because information from a patient's primary tumor may not accurately reflect the metastasis, and one metastasis may vary from another. Furthermore, the variable presence of tumor subpopulations, such as stem cells and dormant cells, may increase the complexity of the targeted treatments needed. Although molecular signatures and circulating biomarkers have been identified in breast cancer, there is lack of validated predictive molecular markers to optimize treatment choices for either prevention or treatment of metastatic disease. Finally, to maximize the information that can be obtained, increased attention to clinical trial design in the metastasis preventive setting is needed. CME Accreditation Statement: This activity ("ASIP 2013 AJP CME Program in Pathogenesis") has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity ("ASIP 2013 AJP CME Program in Pathogenesis") for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. CME Accreditation Statement: This activity ("ASIP 2013 AJP CME Program in Pathogenesis") has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity ("ASIP 2013 AJP CME Program in Pathogenesis") for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity. CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. Although personalizing the treatment of breast and other cancers is a promising goal, individualizing treatments will require a wealth of new molecular data and therapeutic options. Much of the recent progress has been in personalizing treatment of early breast cancer. These efforts have moved beyond already established therapies for patients with estrogen receptor–positive (ER+) and/or progesterone receptor–positive (PR+) and HER2-overexpressing (HER2+) disease, primarily using multigene assays that are prognostic for risk of recurrence and predictive for response to cytotoxic chemotherapy. Personalized medicine for metastatic disease presents greater hurdles, however. The complexity, heterogeneity, and genomic instability of metastatic breast cancer cells make their evaluation and therapy a challenging process (Table 1). Thus, although this review sheds light on potentially important aspects of personalized medicine in metastatic breast cancer, the potential remains to be realized.Table 1Hallmarks of Metastasis and Their Implications for Personalized MedicineHallmarkImplications for Personalized MedicineHeterogeneity between primary tumors and metastases, and among metastasesTherapy based on primary tumor characteristics may not be effectiveRedundancy of mechanistic pathwaysNeed for combination therapiesVariable dormancyClinical trials must address delayed relapsesContributions of cancer-initiating cellsIncorporation of therapies that target stem cells Open table in a new tab Metastasis has been described mechanistically as the migration of tumor cells from the primary tumor, followed by intravasation, survival, extravasation of the circulatory system, and progressive colonization of a distant site.1Steeg P.S. Tumor metastasis: mechanistic insights and clinical challenges.Nat Med. 2006; 12: 895-904Crossref PubMed Scopus (1120) Google Scholar, 2Comen E. Norton L. Massagué J. Clinical implications of cancer self-seeding.Nat Rev Clin Oncol. 2011; 8: 369-377Crossref PubMed Scopus (0) Google Scholar, 3Welch D.R. Do we need to redefine a cancer metastasis and staging definitions?.Breast Dis. 2006; 26: 3-12Crossref PubMed Google Scholar This mechanistic description does not capture other equally valid characteristics, however. In a second definition, that of parallel progression, the defining feature is tumor cell genomic instability, promoting selection for characteristics that enable invasion and distant organ colonization.4Klein C.A. Parallel progression of primary tumours and metastases.Nat Rev Cancer. 2009; 9: 302-312Crossref PubMed Scopus (480) Google Scholar From this perspective, it is not the steps in metastasis that are critical, but rather the instability that fuels the process. In yet another definition, metastasis is described in terms of seed and soil.5Paget S. The distribution of secondary growths in cancer of the breast. 1889.Cancer Metastasis Rev. 1989; 8: 98-101PubMed Google Scholar Tumor cells (seeds) spread widely through the body, but grow only in supportive locations (congenial soil). Thus the various microenvironments (soils) of metastases contribute to the observed heterogeneity. Layered over the fundamentals of the metastatic process is acquired or innate resistance to therapies. Because only 5% of breast cancer patients have stage IV disease at initial diagnosis (http://www.seer.cancer.gov/statfacts/html/breast.html; accessed February 1, 2013), in the majority of metastatic patients the metastatic disease develops after hormone therapy, chemotherapy, or biologics have been used in adjuvant treatment. Another hallmark of metastasis is the redundancy of pathways that mediate the process or its component steps. Genes promoting breast cancer metastasis abound, including ERBB2 (alias HER2, NEU), CTNNB1, KRAS, PI3KCA (alias PI3K), EGFR, MYC, TWIST1, SNAI1 (alias SNAIL), SNAI2, MET, and ID1.6Nguyen D.X. Bos P.D. Massagué J. Metastasis: from dissemination to organ-specific colonization.Nat Rev Cancer. 2009; 9: 274-284Crossref PubMed Scopus (1244) Google Scholar Some genes are involved in tumor cell survival and colonization in the metastatic site in a generalized manner, including PTGS2, EREG, MMP1, LOX, ANGPTL4, and CCL5. Other genes, such as PTHLH (alias PTHRP), IL11, CSF2RB, IL6, and TNF (previously TNFA) function in a more organ-specific manner.6Nguyen D.X. Bos P.D. Massagué J. Metastasis: from dissemination to organ-specific colonization.Nat Rev Cancer. 2009; 9: 274-284Crossref PubMed Scopus (1244) Google Scholar Several of these pathways in genetically engineered mouse models exhibit oncogene addiction, with the ablation of the expression of a single gene causing tumor regression.7Vernon A.E. Bakewell S.J. Chodosh L.A. Deciphering the molecular basis of breast cancer metastasis with mouse models.Rev Endocr Metab Disord. 2007; 8: 199-213Crossref PubMed Scopus (0) Google Scholar Does this portend better responses to pathway inhibitors? Most pathways are only partial contributors to the metastatic process, meaning that their inhibition would have at-best partial effects and could be overcome by other contributory pathways. Additional pathways suppress metastasis, either by inhibiting tumorigenesis8Sun W. Yang J. Functional mechanisms for human tumor suppressors.J Cancer. 2010; 1: 136-140Crossref PubMed Google Scholar or by specifically suppressing the metastatic process, the latter defined as metastasis suppressor genes.9Steeg P.S. Metastasis suppressors alter the signal transduction of cancer cells.Nat Rev Cancer. 2003; 3: 55-63Crossref PubMed Scopus (363) Google Scholar, 10Smith S.C. Theodorescu D. Learning therapeutic lessons from metastasis suppressor proteins.Nat Rev Cancer. 2009; 9: 253-264Crossref PubMed Scopus (110) Google Scholar Successful personalized medicine approaches will have to deal with the instability, complexity, and multifactorial nature of the metastatic process. Research into the metastatic process is relevant to personalizing both the adjuvant and metastatic clinical settings. In the adjuvant setting, micrometastases are thought to be present, and systemic therapy is administered to prevent their outgrowth. In the metastatic setting, treatment aims to shrink lesions that have completed the metastatic process and to prevent the outgrowth of further metastases. Both preclinical and clinical data suggest that a given drug may not be equally effective in both settings. There appear to be degrees of personalized medicine. Semipersonalized medicine is based on the identification of large groups of patients with certain tumor characteristics that can direct a given patient to corresponding specific types of therapy. True personalized medicine would be based on an individual patient's tumor, directing to a tailored therapy maximized for effectiveness for that one patient in particular. Semipersonalized medicine has already generated effective therapies for groups of patients and thus can provide a basis for personalized approaches. Here, we address three examples: HER2-directed therapies, anti-estrogenic therapies, and bisphosphonate and antibody therapies. The tyrosine kinase receptor proto-oncogene c-ErbB-2 (hereafter referred to by the familiar alias HER2) is overexpressed or amplified in approximately 25% of breast cancers, and is a significant prognostic marker of shorter relapse-free and overall survival.11Slamon D.J. Clark G.M. Wong S.G. Levin W.J. Ullrich A. McGuire W.L. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.Science. 1987; 235: 177-182Crossref PubMed Scopus (7074) Google Scholar HER2 is a transmembrane tyrosine kinase receptor and a member of the EGFR family, which also includes HER1 (EGFR), HER3, and HER4. Additionally, HER2 can interact reversibly with ligand-activated family members to form active heterodimers, leading to phosphorylation of intracellular tyrosine residues. This activation recruits cytoplasmatic signal transducers such as STAT, p85-PI3K, PLC-γ, and Src. Two of the main downstream pathways activated by HER2 are the MAPK and PI3K–AKT pathways promoting cell survival, cell proliferation, and migration.12Hynes N.E. Lane H.A. ERBB receptors and cancer: the complexity of targeted inhibitors.Nat Rev Cancer. 2005; 5 ([Erratum appeared in Nat Rev Cancer 2005, 5:580]): 341-354Crossref PubMed Scopus (2095) Google Scholar HER2+ breast cancer patients derive significant benefit from HER2-targeted therapy, such as the humanized monoclonal antibody trastuzumab combined with chemotherapy in the adjuvant and metastatic settings.13Vogel C.L. Cobleigh M.A. Tripathy D. Gutheil J.C. Harris L.N. Fehrenbacher L. Slamon D.J. Murphy M. Novotny W.F. Burchmore M. Shak S. Stewart S.J. Press M. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer.J Clin Oncol. 2002; 20: 719-726Crossref PubMed Scopus (2306) Google Scholar Although the benefit of trastuzumab-based therapy is undeniable, approximately 50% of HER2-overexpressing breast cancers do not respond to trastuzumab,13Vogel C.L. Cobleigh M.A. Tripathy D. Gutheil J.C. Harris L.N. Fehrenbacher L. Slamon D.J. Murphy M. Novotny W.F. Burchmore M. Shak S. Stewart S.J. Press M. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer.J Clin Oncol. 2002; 20: 719-726Crossref PubMed Scopus (2306) Google Scholar suggesting the need for greater precision. Lapatinib, a small-molecule inhibitor of HER2 and EGFR, has shown efficacy in the metastatic setting after relapse on trastuzumab-based therapy.14Blackwell K.L. Burstein H.J. Storniolo A.M. Rugo H.S. Sledge G. Aktan G. Ellis C. Florance A. Vukelja S. Bischoff J. Baselga J. O'Shaughnessy J. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study.J Clin Oncol. 2012; 30: 2585-2592Crossref PubMed Scopus (280) Google Scholar Several newer therapies aimed at the HER superfamily (EGFR and HER2 to HER4) have been approved or are in late development; these include pertuzumab15Baselga J. Cortés J. Kim S.B. Im S.A. Hegg R. Im Y.H. Roman L. Pedrini J.L. Pienkowski T. Knott A. Clark E. Benyunes M.C. Ross G. Swain S.M. CLEOPATRA Study GroupPertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.N Engl J Med. 2012; 366: 109-119Crossref PubMed Scopus (1126) Google Scholar and trastuzumab emtansine (T-DM1).16Verma S. Miles D. Gianni L. Krop I.E. Welslau M. Baselga J. Pegram M. Oh D.Y. Diéras V. Guardino E. Fang L. Lu M.W. Olsen S. Blackwell K. 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Human epidermal growth factor receptor 2 regulates angiopoietin-2 expression in breast cancer via AKT and mitogen-activated protein kinase pathways.Cancer Res. 2007; 67: 1487-1493Crossref PubMed Scopus (0) Google Scholar It will be of interest to determine whether inhibitors of these pathways, in combination with HER2 therapy, provide a better degree of metastasis prevention or shrinkage of established lesions. At diagnosis, 75% of breast tumors are ER+ and can potentially respond to tamoxifen, aromatase inhibitors, or other hormonal therapies.25Early Breast Cancer Trialists' Collaborative GroupTamoxifen for early breast cancer: an overview of the randomised trials.Lancet. 1998; 351: 1451-1467Abstract Full Text Full Text PDF PubMed Scopus (3393) Google Scholar, 26Mehta R.S. Barlow W.E. Albain K.S. Vandenberg T.A. Dakhil S.R. Tirumali N.R. Lew D.L. Hayes D.F. Gralow J.R. Livingston R.B. Hortobagyi G.N. Combination anastrozole and fulvestrant in metastatic breast cancer.N Engl J Med. 2012; 367: 435-444Crossref PubMed Scopus (186) Google Scholar ER+ tumors tend to metastasize to the bone,27James J.J. Evans A.J. Pinder S.E. Gutteridge E. Cheung K.L. Chan S. Robertson J.F. Bone metastases from breast carcinoma: histopathological–radiological correlations and prognostic features.Br J Cancer. 2003; 89: 660-665Crossref PubMed Scopus (0) Google Scholar and often metastasize late.28Kim R.S. Avivar-Valderas A. Estrada Y. Bragado P. Sosa M.S. Aguirre-Ghiso J.A. Segall J.E. Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer.PLoS One. 2012; 7: e35569Crossref PubMed Scopus (0) Google Scholar A recent long-term follow-up study after 5 years of tamoxifen therapy showed that metastatic relapses continue over the next 10 years and have not leveled off at that time point, suggesting a continuous break from dormancy.29Hackshaw A. Roughton M. Forsyth S. Monson K. Reczko K. Sainsbury R. Baum M. Long-term benefits of 5 years of tamoxifen: 10-year follow-up of a large randomized trial in women at least 50 years of age with early breast cancer.J Clin Oncol. 2011; 29: 1657-1663Crossref PubMed Scopus (52) Google Scholar Estrogen effects are mediated by two specific nuclear receptors, estrogen receptor α (ER-α) and estrogen receptor β (ER-β). ER-α is expressed in breast and is associated with increased proliferation and metastasis. On binding to the ligand, ER regulates the transcription of target genes. ER can also form multiprotein complexes with membrane-related factors such as Src, G-proteins, RTK, and PELP1.30Chakravarty D. Nair S.S. Santhamma B. Nair B.C. Wang L. Bandyopadhyay A. Agyin J.K. Brann D. Sun L.Z. Yeh I.T. Lee F.Y. Tekmal R.R. Kumar R. Vadlamudi R.K. 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Cytokine receptor CXCR4 mediates estrogen-independent tumorigenesis, metastasis, and resistance to endocrine therapy in human breast cancer.Cancer Res. 2011; 71: 603-613Crossref PubMed Scopus (0) Google Scholar The wide range of endocrine therapy options provides an opportunity to select the optimal sequence and combination of therapeutic agents after recurrence or relapse. Current strategies focus on combinations with growth factor and PI3 kinase pathway targeting agents, such as gefitinib and everolimus.35Di Leo A. Malorni L. Polyendocrine treatment in estrogen receptor-positive breast cancer: a "FACT" yet to be proven.J Clin Oncol. 2012; 30: 1897-1900Crossref PubMed Google Scholar, 36Loi S. Michiels S. Baselga J. Bartlett J.M. Singhal S.K. Sabine V.S. Sims A.H. Sahmoud T. Dixon J.M. Piccart M.J. Sotiriou C. 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Breast cancer patients with bone metastases have distinct therapeutic options, including bisphosphonates and (more recently) denosumab, typically in combination with endocrine or HER2-directed therapies. The bone metastatic process has been described as a vicious cycle.38Kang Y. Siegel P.M. Shu W. Drobnjak M. Kakonen S.M. Cordón-Cardo C. Guise T.A. Massagué J. A multigenic program mediating breast cancer metastasis to bone.Cancer Cell. 2003; 3: 537-549Abstract Full Text Full Text PDF PubMed Scopus (1518) Google Scholar Alterations in the bone microenvironment are the initiators of this cycle; major changes include hypoxia, acidic pH, and increased levels of extracellular calcium and growth factors.39Kingsley L.A. Fournier P.G. Chirgwin J.M. Guise T.A. Molecular biology of bone metastasis.Mol Cancer Ther. 2007; 6: 2609-2617Crossref PubMed Scopus (243) Google Scholar The osteolytic vicious cycle is characterized as bone lysis with concurrent infiltration of metastatic tumor cells. TGF-β and parathyroid hormone-related protein (PTHrP) both play an important role in osteolysis. PTHrP, produced by tumor cells, activates osteoblasts and osteoclasts via the RANK ligand (RANKL) pathway, resulting in bone resorption. Bone resorption releases growth factors, ionized calcium, and ionized phosphate. Release of ionized calcium results in an elevation of circulating PTHrP, increasing the propensity for osteolysis by osteoclasts and thus promoting the vicious cycle. Release of growth factors from the bone matrix, such as TGF-β, in turn activates tumor cells, contributing to the cycle.39Kingsley L.A. Fournier P.G. Chirgwin J.M. Guise T.A. Molecular biology of bone metastasis.Mol Cancer Ther. 2007; 6: 2609-2617Crossref PubMed Scopus (243) Google Scholar Denosumab is a human monoclonal antibody against RANKL. In a phase III trial, denosumab reduced the risk of developing multiple skeletal-related events (time to first and subsequent events) by 23%, compared with the bisphosphonate zoledronic acid.40Stopeck A.T. Lipton A. Body J.J. Steger G.G. Tonkin K. de Boer R.H. Lichinitser M. Fujiwara Y. Yardley D.A. Viniegra M. Fan M. Jiang Q. Dansey R. Jun S. Braun A. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.J Clin Oncol. 2010; 28: 5132-5139Crossref PubMed Scopus (788) Google Scholar It must be noted that one consequence of semipersonalized medicine is that some patients will be overtreated, because not all members of the large groups on which semipersonalized treatment is based will benefit alike. Metastatic disease is largely incurable because of the very factors that define it (Figure 1). As precision treatment approaches develop in the adjuvant and metastatic settings, consideration must be given in trial design to these factors: heterogeneity, genomic instability, sites of metastasis, tumor subpopulations, and microenvironmental influences. Recent research has demonstrated heterogeneity in primary tumors and corresponding breast cancer metastases at the morphological, molecular, and genomic levels, and such heterogeneity may be a significant determinant of anticancer therapy response.41Jin K. Teng L. Shen Y. He K. Xu Z. Li G. Patient-derived human tumour tissue xenografts in immunodeficient mice: a systematic review.Clin Transl Oncol. 2010; 12: 473-480Crossref PubMed Scopus (97) Google Scholar Studies evaluating the traditional markers HER2, ER, and PR indicate 5% to 22%, 13% to 33%, and 31% to 32% discordance, respectively, between primary tumor and distant metastases.42Niikura N. Liu J. Hayashi N. Mittendorf E.A. Gong Y. Palla S.L. Tokuda Y. Gonzalez-Angulo A.M. 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Larger studies will be needed to fully assess the frequency and potential benefits of altering therapy because of discordance of tumor characteristics in metastatic sites. For other therapeutic targets, discordance between primary tumors and metastases reigns. Akcakanat et al46Akcakanat A. Sahin A. Shaye A.N. Velasco M.A. Meric-Bernstam F. Comparison of Akt/mTOR signaling in