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Biomarkers for Early Detection and as Surrogate Endpoints in Cancer Prevention Trials: Issues and Opportunities

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Clinical Cancer Prevention

Part of the book series: Recent Results in Cancer Research ((RECENTCANCER,volume 188))

Abstract

In order to improve the early detection and diagnosis of cancer, give more accurate prognoses, stratify individuals by risk, predict response to treatment, and help the transition of basic research into clinical application, biomarkers are needed that accurately represent or predict clinical outcomes. To be useful in trials for chemopreventive agent development, biomarkers must be subject to modulation, easy to obtain and quantify, and have biological meaning, ideally representing steps in well-understood carcinogenic pathways. Though difficult to validate fully, wisely chosen biomarkers in early-phase trials can inform the prioritization of large-scale, long-term trials that measure clinical outcomes. When well-designed, smaller trials using biomarkers as surrogate endpoints should promote faster decisions regarding which targeted preventive agents to pursue, promising greater progress in the personalization of medicine. Biomarkers could become useful in distinguishing indolent from aggressive forms of ductal carcinoma in situ as well as localized invasive breast and prostate cancer, lesions that are often overtreated. Chemopreventive strategies that reduce the progression of early forms of premalignancy can benefit patients not only by reducing their risk of cancer and death from cancer but also by reducing their need for invasive interventions. Genomic and proteomic methods offer the possibility of revealing new potential markers, especially for diseases whose biology is complex or not well understood. Panels of markers may be used to accommodate the molecular heterogeneity of cancers. Biomarkers in phase 2 prevention trials of combinations of chemopreventive drugs have been used to demonstrate synergistic action of multiple agents, allowing use of lower doses, with less toxicity, a critical feature of interventions intended for cancer prevention.

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Abbreviations

AI:

Aromatase Inhibitor

ACS:

American Cancer Society

APC:

Adenoma Prevention with Celecoxib Trial

APC :

Adenomatous polyposis coli gene

BCPT:

Breast Cancer Prevention Trial

Bcl-2:

B cell lymphoma 2 protein

BRCA :

Breast cancer gene

CD10:

A zinc-dependent metalloprotease enzyme

CDH1 :

Cadherin gene

CEA:

Carcinoembryonic antigen

COX2:

Cyclooxygenase 2

CT:

Computed tomography

DCIS:

Ductal carcinoma in situ

DCC :

Deleted in Colorectal Cancer gene

DFMO:

α-difluoromethylornithine

DHT:

Dihydrotestosterone

DNA:

Deoxyribonucleic acid

EDRN:

Early Detection Research Network

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

ETS :

E-twenty six

ETV :

ETS translocation variant

ERG :

ETS related gene

ER-:

Estrogen receptor-negative

ER+:

Estrogen receptor-positive

FDA:

Food and Drug Administration

FHIT :

Fragile Histidine Triad gene

GI:

Gastrointestinal

GGO:

Ground-glass opacity

HbA1C:

Glycated hemoglobin

HER2:

Human epidermal growth factor receptor 2

HPV:

Human papilllomavirus

HRT:

Hormone replacement therapy

IBC:

Invasive breast cancer

IBIS:

International Breast Intervention Study

IEN:

Intra-epithelial neoplasia

IGF-1:

Insulin-like growth factor 1

IGFBP-3:

Insulin-like growth factor binding protein 3

Ki-67:

A protein that in humans is encoded by the MKI67 gene

KRAS :

Kirsten ras sarcoma viral oncogene

LAMR1:

laminin receptor 1

LGD1069:

Bexarotene (Targretin)

MCM2:

Minichromosome maintenance protein

MGMT :

O6-methylguanine–DNA methyltransferase gene

MiB2:

Breast cancer marker of proliferation

NCI:

National Cancer Institute

NLST:

National Lung Screening Trial

NSABP:

National Surgical Adjuvant Breast and Bowel Project

NSAID:

Non-steroidal anti-inflammatory drug

P53:

A tumor suppressor protein that in humans is encoded by the TP53 gene

P16 :

A tumor suppressor gene, also known as cyclin-dependent kinase inhibitor 2A (CDKN2A) gene

PARP:

Poly (ADP-ribose) polymerase

PCNA:

Proliferating cell nuclear antigen

PCA3:

Prostate cancer antigen 3

PCPT:

Prostate Cancer Prevention Trial

PCR:

Polymerase chain reaction

PGP9.5:

Protein gene product 9.5 gene

PLCO:

Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial

PR:

Progesterone receptor

PSA:

Prostate-specific antigen

PSMA:

Prostate-specific membrane antigen

RASSF1A :

Ras ASSociation domain Family 1A gene

RNA:

Ribonucleic acid

RPFNA:

Random periareolar fine-needle aspiration

RXR:

Retinoid X receptor

S100A7:

Protein S100-A7 encoded by the S100A7 gene

SEB:

Surrogate Endpoint Biomarker

SELECT:

Selenium and Vitamin E Cancer Prevention Trial

SERMS:

Selective estrogen receptor modulators

SPINK1:

Pancreatic secretory trypsin inhibitor

STAR:

Study of Tamoxifen and Raloxifene

SWOG:

Southwest Oncology Group

TGFβ:

Transforming growth factor beta

TMPRSS2 :

Transmembrane protease, serine 2

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Acknowledgements

The authors thank Darrell Anderson and Paul Wagner for sharing their insights on biomarkers during the writing of the manuscript. We also thank Lydia Kibiuk for providing graphics expertise in the design of Fig. 3.1.

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Authors and Affiliations

  1. Basic Prevention Science Research Group, Division of Cancer Prevention, National Cancer Institute, 6130 Executive Boulevard, Room 2056, Bethesda, MD, 20892-7340, USA

    Barbara K. Dunn & Peter Greenwald

  2. Garrett Park, Bethesda, MD, USA

    Karin Jegalian

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  1. Barbara K. Dunn
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  2. Karin Jegalian
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Correspondence to Barbara K. Dunn .

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  1. Prävention (ZeTuP), Zentrum für Tumordiagnostik und, Rorschacherstr. 150, St. Gallen, 9006, Switzerland

    Hans-Jörg Senn

  2. Prävention (ZeTuP), Zentrum für Tumordiagnostik und, Rorschacherstr. 150, St. Gallen, 9006, Switzerland

    Florian Otto

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Dunn, B.K., Jegalian, K., Greenwald, P. (2010). Biomarkers for Early Detection and as Surrogate Endpoints in Cancer Prevention Trials: Issues and Opportunities. In: Senn, HJ., Otto, F. (eds) Clinical Cancer Prevention. Recent Results in Cancer Research, vol 188. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-10858-7_3

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