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Use of molecular markers for predicting therapy response in cancer patients

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Abstract

Predictive markers are factors that are associated with upfront response or resistance to a particular therapy. Predictive markers are important in oncology as tumors of the same tissue of origin vary widely in their response to most available systemic therapies. Currently recommended oncological predictive markers include both estrogen and progesterone receptors for identifying patients with breast cancers likely to benefit from hormone therapy, HER-2 for the identification of breast cancer patients likely to benefit from trastuzumab, specific K-RAS mutations for the identification of patients with advanced colorectal cancer unlikely to benefit from either cetuximab or panitumumab and specific EGFR mutations for selecting patients with advanced non-small-cell lung cancer for treatment with tyrosine kinase inhibitors such as gefitinib and erlotinib. The availability of predictive markers should increase drug efficacy and decrease toxicity, thus leading to a more personalized approach to cancer treatment.

Introduction

Because of biological heterogeneity, only a proportion of patients with a particular type of malignancy benefit from a specific treatment. Thus, response rates for patients with different types of advanced cancer to currently available drugs varies from about 10% to >90%.1 Many of the newer biological or so called targeted therapies, in particular, have efficacy in only a minority of patients. Clearly, an ability to prospectively identify patients likely to respond to a specific treatment would be of great clinical value.

Predictive markers are molecules that provide upfront information as to whether or not a patient is likely to benefit from a specific therapy. Predictive markers thus guide the choice of therapy.2 Patients with marker levels indicating a likely response to a specific therapy are potential candidates for undergoing treatment with that therapy. On the other hand, those patients with marker concentrations suggesting resistance could receive an alternative therapy that may be more beneficial. If an effective alternative therapy is unavailable, these patients could volunteer to participate in clinical trials evaluating new therapies or they could make an informed decision to avoid the needless costs and toxicity of likely ineffective therapy.3 As well as assessing efficacy, predictive markers may be able to identify optimum drug dose and predict toxicity. Thus, the availability of predictive markers increase efficacy and decrease toxicity, which in turn, should decrease overall health care costs and result in an enhanced quality of life for patients.4

Predictive markers should not be confused with prognostic markers. Prognostic markers, in contrast to predictive markers, allow the natural course of a specific disease to be predicted.5 They thus differentiate between patients likely to have a good vs. a poor outcome. Candidate prognostic markers for cancer are molecules involved in tumor cell proliferation, dedifferentiation, angiogenesis, invasion or metastasis. On the other hand, predictive markers are likely to be direct targets of drugs, molecules that signal downstream of the primary target, molecules involved in DNA repair or polymorphisms in genes involved in drug metabolism. Examples of predictive markers involved in these processes are listed in Table 1. The aim of this article is to critically review the most widely investigated predictive markers, especially those that are in clinical use or close to entering clinical use. While this review will primarily focus on molecular predictive markers, we would like to state that in certain situations, clinical, demographic and pathological factors may also be associated with response to oncological therapies. This applies especially to patients with non-small-cell lung cancer, see below.

Section snippets

ER and PR for predicting response to hormone therapy in patients with breast cancer

The first and still one of the best therapy predictive markers in oncology is the estrogen receptor (ER), i.e., ER-alpha, which is used in selecting patients with breast cancer for endocrine hormone therapy.6 The original rationale for investigating ER as a predictive marker for hormone therapy was based on the fact that the growth of at least some breast cancers was dependent on estrogens. Since estrogens promoted tumor growth via the ER, it was hypothesised that levels of this receptor in

Cytochrome P450 2D6 in predicting benefit from tamoxifen in breast cancer

One reason why some ER-positive patients fail to respond to tamoxifen therapy may relate to inadequate conversion of the prodrug, tamoxifen to its active metabolite, endoxifen.40 In order to mediate its anti-cancer activity, tamoxifen undergoes metabolism to several metabolites that have variable anti-estrogen activity. The initial activation step involves the conversion of tamoxifen to N-desmethyl tamoxifen. N-desmethyl tamoxifen is then converted to its active form in a reaction catalysed by

HER-2 for predicting response to Trastuzumab and Lapatinib in patients with breast cancer

HER-2 which is also known as c-ErbB2, is a member of the HER (ErbB) transmembrane receptor tyrosine kinase family. Other members of this family include HER-1 (cerbB-1), HER-3 (c-erbB3) and HER-4 (c-erbB4). These 4 receptors have a similar general structure that includes an extracellular domain, a transmembrane domain and an intracellular domain.45 Overexpression of the HER-2 protein which usually results from gene amplification is found in 15–25% of newly diagnosed invasive breast cancers. This

KRAS for predicting response to anti-EGFR antibodies in patients with colorectal cancer

In colorectal cancer (CRC), the HER family member that has been most successfully targeted for treatment is EGFR.66, 67, 68 Similar to HER-2, EGFR stimulates cell growth and survival by signalling through the MAPK, PI3K and JAK/STAT pathways. Two monoclonal antibodies, cetuximab and panitumumab that bind to and inhibit EGFR signalling have been approved for the treatment of advanced chemorefractory CRC. Both these antibodies act by binding to the external domain of EGFR and competitively

EGFR and K-RAS in predicting benefit form tyrosine kinase inhibitors in patients with non-small-cell lung cancer

As in CRC, EGFR has been widely investigated as a therapeutic target in patients with non-small-cell lung cancer (NSCLC).73, 74, 75 Currently, 2 TKIs, gefitinib and erlotinib which target this receptor have been approved for second-line treatment of patients with advanced NSCLC. Results from early phase II studies showed that only about 10% of unselected patients with advanced NSCLC responded to these TKIs (reviewed in Refs. 73, 74, 75). Occasionally, these responses were dramatic, resulting in

Multigene profiles

Historically, single or small numbers of markers have been measured to address a specific clinical problem. In the future however, multi marker profiles, especially genetic profiles are likely to find increasing use. Multigene profiles have now been described for many types of malignancy, especially for breast cancer.30, 31, 32, 33, 34, 35, 92, 93 Two of the best validated gene signatures in breast cancer are the 21-gene recurrence score and the 70-gene (Amsterdam) profiles.92, 93

To-date, these

Emerging predictive markers

In addition to the markers discussed above, there are several emerging oncological therapy predictive markers. Some of these are listed in Table 4. Most of these require further validation before recommendation for clinical use. Furthermore, assays for these markers require optimisation and standardisation prior to clinical use.

Conclusion

It is clear from above that good progress has been made in identifying predictive markers in recent years. Indeed, a number of these markers are currently in everyday clinical use such as ER and PR for identifying patients with breast cancers likely to benefit from hormone therapy, HER-2 for the identification of breast cancer patients likely to benefit from trastuzumab and K-RAS mutation status for the identification of colorectal cancer patients likely to benefit from either cetuximab or

Conflict of interest statement

The authors have no conflict of interest to report.

Acknowledgement

The authors wish to thank Science Foundation Ireland, Strategic Research Cluster award (08/SRC/B1410) to Molecular Therapeutics for Cancer Ireland and the Health Research Board Clinician Scientist Award (CSA/2007/11) for funding this work.

References (116)

  • Y. Kataoka et al.

    Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines

    Ann Oncol

    (2010)
  • Y. Nagata et al.

    PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients

    Cancer Cell

    (2004)
  • R.J. Crowder et al.

    Successful targeting of ErbB2 receptors-is PTEN the key?

    Cancer Cell

    (2004)
  • M.V. Karamouzis et al.

    Targeting MET as a strategy to overcome crosstalk-related resistance to EGFR inhibitors

    Lancet Oncol

    (2009)
  • K.S. Albain et al.

    Prediction of adjuvant chemotherapy benefit in endocrine responsive, early breast cancer using multigene assays

    Breast

    (2009)
  • K.S. Albain et al.

    Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial

    Lancet Oncol

    (2010)
  • M.J. Duffy

    Predictive markers in breast and other cancers: a review

    Clin Chem

    (2005)
  • R.A. Walgren et al.

    Pharmacogenomics discovery approaches: will the real genes please stand up?

    J Clin Oncol

    (2005)
  • J.D. Brenton et al.

    Molecular classification and molecular forecasting of breast cancer: ready for clinical application?

    J Clin Oncol

    (2005)
  • R.S. Huang et al.

    Pharmacogenetics and pharmacogenomics of anticancer agents

    CA Cancer J Clin

    (2009)
  • C.L. Sawyers

    The cancer biomarker problem

    Nature

    (2008)
  • M.J. Duffy

    Estrogen receptors: role in breast cancer

    Crit Rev Clin Lab Sci

    (2006)
  • McGuire WL, Carbone PP, Sears ME, Escher GC. Estrogen receptors in human breast cancer: an overview: In: McGuire WL,...
  • Early Breast Cancer Trialist’s Collaborative Group. Tamoxifen for early breast cancer: an overview of randomized...
  • Early Breast Cancer Trialists’ Collaborative Group (EBCTTG). Effect of chemotherapy and hormone therapy for early...
  • ATAC Trialists Group. Results of the ATCC (Arimidex Tamoxifen, Alone or in Combination) trial after completion of 5...
  • D. Mauri et al.

    Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis

    J Natl Cancer Inst

    (2006)
  • M. Dowsett et al.

    Retrospective analysis of time to recurrence in the ATAC trial according to hormone receptor status

    J Clin Oncol

    (2005)
  • P.E. Goss et al.

    Efficacy of letrozole extended adjuvant therapy according to estrogen receptor and progesterone receptor status of the primary tumor: National Institute of Canada Clinical Trials Group MA.17

    J Clin Oncol

    (2007)
  • H. Takei et al.

    Multicenter phase II trial of neoadjuvant exemestane for postmenopausal patients with hormone receptor-positive, operable breast cancer: Saitama Breast Cancer Clinical Study Group (SBCCSG-03)

    Breast Cancer Res Treat

    (2008)
  • E.A. Musgrove et al.

    Biological determinants of endocrine resistance in breast cancer

    Nature Rev Cancer

    (2009)
  • K.B. Horwitz et al.

    Predicting response to endocrine therapy in human breast cancer: a hypothesis

    Science

    (1975)
  • P.M. Ravdin et al.

    Prognostic metastatic breast cancer treated with tamoxifen: results of a prospective Southwest Oncology Group study

    J Clin Oncol

    (1992)
  • V.J. Bardou et al.

    Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in 2 large breast cancer databases

    J Clin Oncol

    (2003)
  • M. Stendahl et al.

    High progesterone receptor expression correlates to the effect of adjuvant tamoxifen in premenopausal breast cancer patients

    Clin Cancer Res

    (2006)
  • S. De Placido et al.

    Twenty-year results of the Naples GUN randomized trial: predictive factors of adjuvant tamoxifen efficacy in early breast cancer

    Clin Cancer Res

    (2003)
  • M. De Laurentiis et al.

    A meta-analysis of the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer

    Clin Cancer Res

    (2005)
  • J.M. Giltnane et al.

    Quantitative measurement of epidermal growth factor receptor is a negative predictive factor for tamoxifen response in hormone receptor positive premenopausal breast cancer

    J Clin Oncol

    (2007)
  • J. Foekens et al.

    Urokinase-type plasminogen activator and its inhibitor PAI-1: predictors of poor response to tamoxifen therapy in recurrent breast cancer

    J Natl Cancer Inst

    (1995)
  • M.E. Meijer-van Gelder et al.

    Urokinase-type plasminogen activator (uPA) system in breast cancer: association with tamoxifen therapy in recurrent disease

    Cancer Res

    (2004)
  • S. Paik

    Development and clinical utility of a 21-gene recurrence score prognostic assay in patients with early breast cancer treated with tamoxifen

    Oncologist

    (2007)
  • S. Paik et al.

    A multi-gene assay to predict recurrence of tamoxifen-treated node-negative breast cancer

    N Engl J Med

    (2005)
  • M. Dowsett et al.

    Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study

    J Clin Oncol

    (2010)
  • M.P.H.M. Jansen et al.

    HOXB13-to-IL17BR expression ratio is related with tumor aggressiveness and response to tamoxifen of recurrent breast cancer: a retrospective study

    J Clin Oncol

    (2007)
  • Y. Zhang et al.

    The 76-gene signature defines high-risk patients that benefit from adjuvant tamoxifen therapy

    Breast Cancer Res Treat

    (2009)
  • E. Vegeto et al.

    Human progesterone A form is a cell and promoter-specific repressor of human progesterone receptor B function

    Mol Endocrinol

    (1993)
  • D.X. Wen et al.

    The A and B form of human progesterone receptor operate through distinct signalling pathways within target cells

    Mol Cell Biol

    (1994)
  • T.A. Hopp et al.

    Breast cancer patients with progesterone receptor PR-A rich tumors have poorer disease-free survival rates

    Clin Cancer Res

    (2004)
  • J.M. Hoskins et al.

    CYP2D6 and tamoxifen: DNA matters in breast cancer

    Nat Rev Cancer

    (2009)
  • Y. Jin et al.

    CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment

    J Natl Cancer Inst

    (2005)
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