Emerging strategies for therapeutic targeting of the tumour microenvironment



  1. Ocular Oncology Unit, Save Sight Institute, University of Sydney, New South Wales, Australia.
  2. School of Optometry and Vision Science, University of New South Wales, New South Wales, Australia.
  3. The Kinghorn Cancer Centre, St Vincent’s Hospital and UNSW Clinical School, Darlinghurst, New South Wales, Australia.


Metastatic cancers are often resistant to conventional chemotherapy and radiotherapy, reflecting an unmet need for novel therapeutic approaches to inhibit metastasis. Growing evidence highlights the importance of targeting not only the tumour but also its ‘normal’ microenvironment – the milieu which surrounds the tumour, including stromal fibroblasts, infiltrating immune cells, blood vessels, signalling molecules, extracellular matrix and tissue oxygen. The microenvironment varies between different organs, presumably explaining the propensity of certain cancers to spread to particular sites. This review summarises current and emerging therapies targeting the metastatic microenvironment in human tumours. The role of the tumour microenvironment in the establishment and support of metastatic disease is increasingly evident. Novel therapeutic strategies targeting the microenvironment encompassing the complex interactions between tumour cells and surrounds now need to be incorporated into clinical trials with appropriate biomarker endpoints.

Metastasis and the tumour microenvironment

Cancer metastases account for over 90% of mortality in cancer patients.1 As such research into the causes of metastases has the potential to yield novel therapeutic targets. Recent research into the oncogenic role of the tumour microenvironment has begun to reveal new insights, triggering the evolution of a paradigm shift in the way we understand and treat metastatic cancers.

Metastasis occurs when a cancer cell undergoes changes allowing extravasation and colonisation at a distant location to form one or more secondary tumour clones. We envisage metastasis as a complex and multistep process – the metastatic cascade – involving loss of tumour cellular adhesion, local tissue invasion, extravasation and survival in the circulation, movement into new tissue and eventually colonisation of a distant site.2-4 In theory, any step(s) in the metastatic cascade could be targeted, however certain steps can occur prior to the clinical manifestation of the metastatic disease prior to clinical presentation of overt metastatic disease, potentially rendering palliative treatments targeting the later steps ineffective.5 Targeting the site of metastatic colonisation may thus prove to be an important strategy in preventing the emergence and/or progression of metastatic disease.

The tumour microenvironment encompasses the milieu surrounding a tumour cell, including stromal fibroblasts, blood and lymphatic vessels, infiltrating immune cells, signalling molecules, tissue oxygen and components of the extracellular matrix (figure 1).6 The tumour microenvironment varies between different organs,3 which may explain the tendency of certain primary cancers to metastasise to particular sites.6 Cancer cells can communicate with and alter their microenvironment, establishing molecular changes that encourage the metastatic colonisation of cancer cells. For example, in a study that grafted cancer cells into mice with either normal fibroblasts, or cancer-associated fibroblasts, cancer proliferation was only apparent in mice with the cancer-associated fibroblasts.7 Therapeutic targeting of the tumour microenvironment is thus an increasingly attractive strategy to prevent or treat metastatic cancer. Furthermore, the genetic stability of the microenvironment compared to the metastatic tumour itself makes it a favourable target for minimising resistance.6 What still remains unclear however, is how the tumour microenvironment – ‘normal’ as this is widely assumed to be – may be both selectively, yet tolerably, targeted.

Figure 1: Schematic diagram showing the milieu surrounding tumour cells

Cells in the microenvironment may communicate both positive and negative signals to the tumour cells, resulting in establishment of a pro- or anti-tumour microenvironment respectively. Proteins derived from exosomes released by melanoma cells for example, can enhance the metastatic microenvironment via promotion of pro-inflammatory and pro-angiogenic properties of bone-marrow derived progenitor cells, providing a metastatic niche.8 Similar events can lead to upregulation of factors in sentinel lymph nodes that potentiate extracellular matrix production and migration of melanoma cells to these.9Further to this, it has been suggested that ‘re-education’ of stromal cells to provide an anti-tumour environment may be a more effective strategy than non-selectively ablating tumour-associated stromal cells in controlling metastatic disease.6 In this review we describe some current and emerging approaches to targeting the metastatic microenvironment for several cancers (table 1).

Table 1: Examples of potential metastatic cancer microenvironment targets and strategies for current and emerging therapies

Prostate cancer

Prostate cancer, the most common non-skin cancer in Australian men, preferentially metastasises to bone, often resulting in abnormal bone formation (osteosclerosis), fractures, pain and neural compression.10 Newly diagnosed prostate cancers tend to be dependent on stimulation via the androgen receptor for survival and proliferation. Medical prostate cancer therapy therefore first involves targeting the cancer cells via androgen deprivation therapy such as orchiectomy or pharmacological castration, for example using gonadotropin-releasing hormone agonists or antagonists.11 Although androgen deprivation therapy tends to be initially effective, most prostate cancers relapse within a few months or years, progressing to castrate-resistant prostate cancer. Chemotherapy (for example, using docetaxel or cabazitaxel) remains a key treatment for castrate-resistant prostate cancer.12 However, treatment-induced damage to the tumour microenvironment may swiftly promote resistance to standard chemotherapy,13 for example, by inducing tumour cell epithelial-mesenchymal transition,14 with associated changes in gene expression profile.

Targeting cells in the bone microenvironment is also useful in the treatment of metastatic castrate-resistant prostate cancer. Osteoblasts in bone express the protein RANK-L, which is responsible for the activation of osteoclasts. In prostate cancer, RANK-L is upregulated in osteoblasts, osteocytes and fibroblasts in bone in response to tumour-secreted growth factors, leading to release of growth factors from bone matrix that may promote the development of skeletal metastases.15 Denosumab, a monoclonal antibody against RANK-L, appeared to inhibit castrate-resistant prostate cancer metastasis to bone in a phase III trial.15 Radium-223, an alpha-emitting calcium mimetic radioisotope that selectively binds the hydroxyapatite moiety of the osteoblastic microenvironment, also unexpectedly prolongs survival compared to placebo, consistent with a changing paradigm of how direct modulation of the metastatic microenvironment may impact on disease natural history.16

Immune cells in the microenvironment are important potential therapeutic targets. The host immune response can induce tumour suppression, but this response is generally ineffective due to local secretion of immunosuppressive agents.17 For example, T-lymphocytes express the membrane protein CTLA-4, which when activated, downregulates activity of the immune system. Ipilimumab, a monoclonal antibody to CTLA-4, promotes T-cell activation, allowing the immune system to destroy cancer cells.17,18 Preliminary studies of ipilimumab have demonstrated anti-tumour activity in patients with metastatic castrate-resistant prostate cancer.18,19 Immune cells are similarly targeted by sipuleucel-T therapy, an ex vivo autologous cellular immunotherapy derived from a patient’s own peripheral leukocytes.20 The extracted leukocytes are incubated with a fusion protein consisting of a prostate cancer antigen recombinantly linked to granulocyte-macrophage colony stimulating factor. Following this ex vivo activation, the blood product is reinfused into the patient to elicit an immune response against the prostate cancer cells.20 Intriguingly, despite relatively modest tumourolytic activity and prostate specific antigen (PSA) response rates, sipuleucel-T treatment has been associated with clear improvements in overall survival, and is the first successful vaccination-based approach for prostate cancer.20

Breast cancer

Breast cancer is the most common cancer in Australian women, excluding non-melanoma skin cancer, and is the second leading cause of cancer-related death in Australian women. Three main receptors are used to classify breast cancers: the oestrogen receptor (ER); the progesterone receptor (PR); and human epidermal growth factor receptor (EGFR) type 2 (HER2).21 The pattern of metastatic spread in breast cancer is dependent on the receptors present on the cancer cells,22 with bone being the most common site of metastases.23

ER- and PR-positive cancer cells are typically dependent on hormonal signalling for growth in metastatic sites ab initio, and adjuvant hormonal therapies are effective in reducing the frequency of micrometastatic spread of these breast cancers.24 ER-positive lobular carcinomas, which do not express the epithelial-stromal adhesion factor E-cadherin, metastasise more often to serosal surfaces (for example, pleura and peritoneum) than do invasive ductal cancers. 25

The survival benefits of adjuvant cytotoxic therapy, particularly in ER-negative premenopausal patients with lymph node metastases,26 have been associated with indicators of stromal toxicity such as neutropaenia,27 consistent with a therapeutic role for paracrine loop disruption. The small but significant survival benefit associated with post-mastectomy radiotherapy, suggests further that the cytotoxic modulation of the local peritumoral microenvironment may improve not only local recurrence rates, but also frequencies of distant relapse.28

Chemotherapy combined with adjuvant anti-HER2 humanised monoclonal antibody, significantly improves clinical outcomes and survival for patients with HER2-positive metastatic breast cancer.29,30 Metastatic disease often progresses and resistance to HER2 antibody can be encountered over time; alternative therapies and targets are thus being explored. Recent studies have used chemotherapy with adjuvant combinations of HER2 antibodies (trastuzumab and pertuzumab) that target different regions of the receptor and found clinical efficacy.31 Dual inhibitors of EGFR, HER2 and HER4 (such as lapatinib, afatinib and neratinib) are also being trialled for metastatic breast cancer.32

Approximately 10% to 15% of women with metastatic breast cancer will develop brain metastases, patients with HER2-positive or triple-negative breast cancer being more susceptible. Conventional systemic therapies are limited in this context related to blood-brain barrier (BRB) permeability. Novel approaches are currently being explored including BRB permeable cytotoxic agents, physical disruption of the BRB, and HER2-directed therapies.33

Bone metastases in breast cancer tend to result in abnormal bone resorption (osteolysis), predisposing to pathological fractures, in contrast to the bone formation (osteosclerosis) noted above for observed for metastatic prostate cancer. Bisphosphonates or denosumab are used concurrently to reduce metastatic bone complications and/or to counteract the osteoporotic effects of long-term aromatase-inhibitory hormonal therapy.34 Interestingly, the bone metastases microenvironment may induce HER2 expression, regulated by the RANK-L protein discussed above, with potential for stimulating breast cancer stem cells and bone micrometastasis.35,36

Hypoxic conditions, such as may be found in bone metastases, can lead to production of vascular endothelial growth factor (VEGF), and tumour-related vessel growth. However, despite this plausible rationale for targeted therapy, adjuvant use of bevacizumab (VEGF antibody) with chemotherapy for breast cancer metastases does not increase overall survival,37 is associated with increased adverse outcomes, and is not indicated for metastatic breast cancer. This lack of preventative adjuvant efficacy is also true of small-molecule kinase-inhibitory anti-angiogenic drugs such as sorafenib and sunitinib.38,39

There is also evidence for reduced rates of breast cancer incidence and post-primary recurrence, associated with non-pharmacological modulation of the normal metabolic microenvironment by interventions such as weight loss and / or physical activity.40,41These interventions appear to work via several physiological microenvironment-related processes, including altering the circulating hormone levels, and regulating various growth factor and/or apoptosis-related signalling pathways.42

Colorectal cancer

Colorectal cancer is the second most commonly diagnosed cancer in Australia, and often metastasises to multiple sites, including the liver.43 Bevacizumab is of clinical value when used together with chemotherapy in the palliative, but not adjuvant, setting for metastatic colorectal cancer.44,45 Similarly, antibodies to the epidermal growth factor receptor (EGFR) pathway, such as cetuximab or panitumumab, are effective as tumourolytic drugs for cancers that lack constitutively activating KRAS mutations (wild-type KRAS tumours).46,47 However, EGFR overexpression or amplification in colorectal cancer biopsies is not consistently predictive of cetuximab efficacy.48,49 Several gene polymorphisms have been identified as positive outcome predictors in patients with wild-type KRAS tumours that are not cetuximab-responsive.49,50 Early onset of skin toxicity (within two weeks of starting treatment) predicts a better response to cetuximab in colorectal cancer patients.51 Although the mechanism for the severe skin toxicity has not been clearly identified, cytokine regulatory changes in skin (and tumour) microenvironment related to EGFR inhibition have been suggested.52

Regorafenib, an oral small molecule multi-kinase inhibitor, can inhibit a wide range of stromal, angiogenic and tumour-related receptor tyrosine kinases that may be important for the metastatic cascade, including promotion of new tumour vessels and lymphatic vessel formation. Recent studies show clinical benefits (prolonged survival) of regorafenib for patients with progressive metastatic colorectal cancer who have been treated previously with standard cytotoxic agents and targeted therapies.53 Preclinical observations discussed above, suggested that regorafenib regulates processes important in the tumour microenvironment, although the mechanisms involved clinically are not fully understood.

Lung cancer

Lung cancer is the leading cause of cancer death in Australian men and women. Palliative systemic therapy for lung cancer includes anti-mitotic compounds such as cisplatin, carboplatin or taxanes.54 Molecular drug targets with demonstrated efficacy include the EGFR pathway (erlotinib/gefitinib), and the VEGF pathway.

Hypoxic conditions in the cancer microenvironment can increase the risk of metastasis,55making hypoxia and its metabolic responses potential therapeutic targets. Hypoxia stabilises the hypoxia-induced factor (HIF) family of proteins, which bind to HIF-response elements, upregulating proteins involved in angiogenesis (in particular, VEGF) and tumour invasion.55,56 HIF-1 is overexpressed in 60% of non-small cell lung cancers, and is predictive of a poor overall survival.57 Targeting HIF family proteins could potentially reduce production of downstream proteins such as VEGF, important in tumour growth and the metastatic cascade. A study investigating the effects of PX-478, a small molecule inhibitor of HIF-1 protein synthesis, found reduced tumour volume and metastatic spread in a mouse model of small-cell lung cancer.58 Phase I clinical trials have found that oral PX-478 is well tolerated, and further trials are now needed to evaluate its effectiveness in a clinical setting.59

Hypoxia can also induce tumour resistance to radiotherapy via the action of antioxidants which repair the radiation-induced DNA strand breaks.60,61 This is relevant to management of cerebral metastases, which often involves whole brain radiotherapy. Efaproxiral, a drug that allosterically modifies haemoglobin by reducing its oxygen binding affinity, may facilitate the release of oxygen to tissues, mitigating radiotherapy resistance in hypoxic tumours.62 However, phase III clinical trials investigating whole brain radiotherapy and adjuvant efaproxiral for the treatment of brain metastases from lung cancer have not, to date, found an improvement in overall survival compared to treatment with whole brain radiotherapy alone.63


Cutaneous melanoma is the fourth most common cancer in Australia, accounting for 3% of all skin cancers, but 75% of skin cancer-related deaths. Melanoma cells can spread throughout the body at early stages and the prognosis in metastatic disease remains poor. Recent studies targeting the BRAF/MEK pathway via inhibitors of the mutated BRAF kinase in patients with metastatic cutaneous melanoma have been associated with dramatic responses, and modestly improved overall survival, including those with brain metastases.64,65 Immunotherapy with the T-cell-activating CTLA4 antagonist ipilimumab, causes fewer responses but does seem to lead to greater survival gains,66 emphasising the importance of ‘off-target’ effects (in this case, immune regulation) in modulating tumour natural history.
Uveal melanoma (affecting the inner vascular pigmented layer of the eye) is the most common primary eye tumour in adults,67 and as with cutaneous melanoma, metastatic disease is associated with a poor prognosis. Intriguingly, liver metastases are seen in 95% of uveal melanoma patients with metastatic disease,68 suggesting possible therapeutic targets within the liver microenvironment. Immunotherapy using ipilimumab is currently being trialled for patients with metastatic uveal melanoma.
Metastatic disease in both cutaneous and uveal melanoma shows poor responses to conventional chemotherapeutics such as dacarbazine,69 indicating a need for new treatment strategies targeting the tumour-host interface.


National Foundation for Medical Research and Innovation.


  1. Mehlen P, Puisieux A. Metastasis: a question of life or death. Nat Rev Cancer. 2006;6(6):449-58.
  2. Fidler IJ. Understanding bone metastases: the key to the effective treatment of prostate cancer. Clin Adv Hematol Oncol. 2003 1:278-9.
  3. Gupta GP Massagué J. Cancer metastasis: building a framework. Cell. 2006 127(4):679-695.
  4. Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011 147(2):275-292.
  5. Mina LA, Sledge GW Jr. Rethinking the metastatic cascade as a therapeutic target. Nat Rev Clin Oncol. 2011;8(6):325-32.
  6. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19(11):1423-1437.
  7. Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature. 2004;432(7015):332-337.
  8. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012 18(6):883-891.
  9. Hood JL, San RS, Wickline SA. Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis.Cancer Res. 201171(11):3792-3801.
  10. Bubendorf L, Schopfer A, Wagner U, Sauter G, Moch H, Wili N, et al. Metastatic patterns of prostate cancer: an autopsy study of 1589 patients. Hum Pathol. 2000;31:578-583.
  11. Kunath F, Keck B, Antes G, Wullich B, Meerpohl JJ. Tamoxifen for the management of breast events induced by non-steroidal antiandrogens in patients with prostate cancer: a systematic review. BMC Med. 2012;10:96.
  12. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512.
  13. Sun Y, Capisi J, Higano C, Beer TM, Porter P, Coleman I, et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med. 2012;18(9):1359-1368.
  14. Marín-Aguilera M, Codony-Servat J, Reig O, Lozano JJ, Fernández PL, Pereira MV, et al. EMT; Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer.Mol Cancer Ther. 2014 May;13(5):1270-1284.
  15. Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2013;379(9810):39-46.
  16. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. N Engl J Med. 2013;369(3):213-223.
  17. Schweizer MT, Drake CG. Immunotherapy for prostate cancer: recent developments and future challenges. Cancer Met Rev. 2014; doi:10.1007/s10555-013-9479-8.
  18. Small E, Higano C, Tchekmedyian N, Sartor O, Stein B, Young R, et al. Randomised phase II study comparing 4 monthly doses of ipilimumab (MDX-010) as a single agent or in combination with a single dose of docetaxel in patients with hormone-refractory prostate cancer. J Clin Oncol. 2006;24 Suppl 18:4609.
  19. Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label multicenter phase I/II study. Ann Oncol. 2013;24(7):1813-1821.
  20. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-22.
  21. Prat A, Perou CM. Deconstructing the molecular portraits of breast cancer. Mol Oncol. 2011;5(1):5-23.
  22. Lekanidi K, Evans AL, Shah J, Jaspan T, Baker L, Evans AJ. Pattern of brain metastatic disease according to HER-2 and ER receptor status in breast cancer patients. Clin Radiol. 2013;68(10):1070-1073.
  23. Kennecke H, Yerushalmi R, Woods R, Cheang MC, Voduc D, Speers CH, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol. 2010;28(20):3271-3277.
  24. Early Breast Cancer Trialists’ Collaborative Group (EBCTG) Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Lancet. 2011 378(9793):771-784.
  25. Fondrinier E, Guérin O, Lorimier G. Bull Cancer. A comparative study of metastatic patterns of ductal and lobular carcinoma of the breast from two matched series (376 patients) 1997 84(12):1101-1107.
  26. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Clarke M, Coates AS, Darby SC, Davies C, Gelber RD, Godwin J et al. Adjuvant chemotherapy in oestrogen-receptor-poor breast cancer: patient-level meta analysis of randomised trials. Lancet. 2008; 371(9606):29-40.
  27. Cameron DA, Massie C, Kerr G, Leonard RC. Moderate neutropenia with adjuvant CMF confers improved survival in early breast cancer. Br J Cancer. 2003 89(10):1837-1842.
  28. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Darby S, McGale P, Correa C, Taylor C, Arriagada R, Clarke M et al. Effect of radiotherpay after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011; 378(9804):1707-1716.
  29. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A et al. Use of chemotherapy plus monoclonal antibody against HER2 for metastatic breast that overexpresses HER2. N Engl J Med. 2001; 344(11):783-792.
  30. Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005; 23(19):4265-4274.
  31. Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH et al. CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-119.
  32. Tsang RY, Finn RS. Beyond trastuzumab: novel therapeutic strategies in HER2-positive metastatic breast cancer. Br J Cancer 2012 106(1):6-13.
  33. Lin NU, Amiri-Kordestani L, Palmieri D, Liewehr DJ, Steeg PS. CNS metastases in breast cancer: old challenge, new frontiers. Clin Cancer Res. 2013 19(23):6404-6418.
  34. Steger GG, Bartsch R. Denosumab for the treatment of bone metastases in breast cancer: evidence and opinion. Ther Adv Med Oncol. 2011;3(5):233-243.
  35. Korkaya H, Wicha MS. HER2 and breast cancer stem cells: more than meets the eye. Cancer Res 2013;73: 3489-3493.
  36. Geng SQ, Alexandrou AT, Li JJ. Breast cancer stem cells: multiple capacities in tumour metastasis. Cancer Lett 2014;349(1):1-7.
  37. Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, et al. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012;366(4):310-320.
  38. Bergh J, Bondarenko IM, Lichinitser MR, Liljegren A, Greil R, Voytko NL, et al. First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomised phase III study. J Clin Oncol. 2012;30(9):921-929.
  39. Gradishar WJ, Kaklamani V, Sahoo TP, Lokanatha D, Raina V, Bondarde S, et al. A double-blind, randomised, placebo-controlled, phase 2b study evaluating sorafenib in combination with paclitaxel as a first-line therapy in patients with HER2-negative advanced breast cancer. Eur J Cancer. 2013;49(2):312-322.
  40. Lynch BM, Friedenreich CM, Winkler EA, Healy GN, Vallance JK, Eakin EG et al. Associations of objectively assessed physical activity and sedentary time with biomarkers of breast cancer risk in postmenopausal women: findings from NHANES (2003-2006). Breast Cancer Res Treat. 2011 130(1):183-194.
  41. Neilson HK, Conroy SM, Friedenreich CM. The Influence of energetic factors on biomarkers of postmenopausal breast vancer risk. Curr Nutr Rep. 2013;3:22-34.
  42. Eccles SA, Aboagye EO, Ali S, Anderson AS, Armes J, Berditchevski F, et al., critical research gaps and translational priorities for the successful prevention and treatment of breast cancer. Breast Cancer Res. 2013;15(5):R92.
  43. Patanaphan V, Salazar OM. Colorectal cancer: metastatic patterns and prognosis. South Med J. 1993;86(1):38-41.
  44. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for Metastatic Colorectal Cancer. N Engl J Med. 2004;350(23):2335-2342.
  45. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, Prausová J, Macarulla T, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499-3506.
  46. Prenen H, Vecchione L, Van Cutsem E. Role of targeted agents in metastatic colorectal cancer. Target Oncol. 2013;8(2):83-96.
  47. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337-345.
  48. Chung KY, Shia J, Kemeny NE, Shah M, Schwartz GK, Tse A et al. Cetuximab shows activity in colorectal cancer patients with tumours that do not express the epidermal growth factor receptor activity in immunohistochemistry. J Clin Oncol. 2005;23(9):1803-1810.
  49. Baker JB, Dutta D, Watson D, Maddala T, Munneke BM, Shak S et al. Tumour gene expression predicts repsonse to cetuximab in patients with KRAS wild-type metastatic colorectal cancer. Br J Cancer. 2011;104(3):488-495.
  50. Winder T, Zhang W, Yang D, Ning Y, Bohanes P, Gerger A et al. Germline polymorphisms in genes involved in the IGF1 pathway predict efficacy of cetuximab in wild-type KRAS mCRC patients. Clin Cancer Res. 2010 16(22):5591-5602.
  51. Kogawa T, Doi A, Shimokawa M, Fouad TM, Osuga T, Tamura F, et al. Early skin toxicity predicts better outcomes, and early tumor shrinkage predicts better response after cetuximab treatment in advanced colorectal cancer. Target Oncol. 2014 May 27. [Epub ahead of print]
  52. Paul T, Schumann C, Rüdiger S, Boeck S, Heinemann V, Kächele V et al. Cytokine regulation by epidermal growth factor receptor inhibitors and epidermal growth factor receptor inhibitor associated skin toxicity in cancer patients. Eur J Cancer. 2014 S0959-8049(14)00630-3.
  53. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312.
  54. Albain KS, Swann RS, Rusch VW, Turrisi AT 3rd, Shepherd FA, Smith C, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet. 2009;374(9687):379-386.
  55. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.
  56. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721-732.
  57. Yang Y, Sun M, Wang L, Jiao B. HIFs, angiogenesis, and cancer. J Cell Biochem. 2013;114(5):967-974.
  58. Jacoby JJ, Erez B, Korshunova MV, Williams RR, Furutani K, Takahashi O, et al. Treatment with HIF-1α antagonist PX-478 inhibits progression and spread of orthotopic human small cell lung cancer and lung adenocarcinoma in mice. J Thorac Oncol. 2010;5(7):940-949.
  59. Tibes R, Falchook GS, Von Hoff DD, Weiss GJ, Lyengar T, Kurzrock R, et al. Results from a phase I, dose-escalation study of PX-478, an orally available inhibitor of HIF-1α. J Clin Oncol. 2010;28(15s):3076.
  60. Graves EE, Maity A, Le QT. The tumor microenvironment in non-small cell lung cancer. Semin Radiat Oncol. 2010;20(3):156-163.
  61. Meijer TW, Kaanders JH, Span PN, Bussink J. Targeting hypoxia, HIF-1, and tumor glucose metabolism to improve radiotherapy efficacy. Clin Cancer Res. 2012;18(20):5585-94.
  62. Suh JH, Stea B, Nabid A, Kresl JJ, Fortin A, Mercier JP, et al. Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases. J Clin Oncol. 2006;24(1):106-114.
  63. Suh JH, Stea B, Tankel K, Marsiglia H, Belkacemi Y, Gomez H, et al. Results of the phase III ENRICH (RT-016) study of efaproxiral administered concurrent with Whole Brain Radiation Therapy (WBRT) in women with brain metastases from breast cancer. Int J Radiat Oncol Biol Phys. 2008;72(1):S50-1.
  64. Chapman PB, Hauschild A, Robert C, Haanen B, Ascierto P, Larkin J et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516.
  65. McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15(3):323-332.
  66. Queirolo P, Spagnolo F, Ascierto PA, Simeone E, Marchetti P, Scoppola A, et al. Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases. J Neurooncol. 2014;118(1):109-116.
  67. Collaborative Ocular Melanoma Study Group. Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the Collaborative Ocular Melanoma Study (COMS): COMS Report No. 15. Arch Ophthalmol. 2001;119(5):670-676.
  68. Aubin JM, Rekman J, Vandenbroucke-Menu F, Lapointe R, Fairfull-Smith RJ, Mimeault R, et al. Systematic review and meta-analysis of liver resection for metastatic melanoma. Br J Surg. 2013;100(9):1138-1147.
  69. Augsburger JJ, Correa ZM, Shaikh AH. Quality of evidence about effectiveness of treatments for metastatic uveal melanoma. Trans Am Ophthalmol Soc. 2008;106:128-135.

Be the first to know when a new issue is online. Subscribe today.