Abstract
Advances in our understanding of the intricate molecular mechanisms for transformation of a normal cell to a cancer cell, and the aberrant control of complementary pathways, have presented a much more complex set of challenges for the diagnostic and therapeutic disciplines than originally appreciated. The oncology field has entered an era of personalized medicine where treatment selection for each cancer patient is becoming individualized or customized. This advance reflects the molecular and genetic composition of the tumors and progress in biomarker technology, which allow us to align the most appropriate treatment according to the patient's disease. There is a worldwide acceptance that advances in our ability to identify predictive biomarkers and provide them as companion diagnostics for stratifying and subgrouping patients represents the next leap forward in improving the quality of clinical care in oncology. As such, we are progressing from a population-based empirical 'one drug fits all' treatment model, to a focused personalized approach where rational companion diagnostic tests support the drug's clinical utility by identifying the most responsive patient subgroup.
Key Points
-
Cancer is a diverse collection of diseases that have different causative factors, molecular composition, and natural histories
-
Many recently developed cancer drugs target discrete molecular aberrations or pathways in tumor cells and consequently are active on a subset of the patient population
-
Companion diagnostics that measure biomarkers that allow responsive patients to be identified and subgrouped are being increasingly integrated with the drug-development process and clinical trials
-
Most response-specific biomarkers that have reached clinical validation were identified through retrospective analysis of clinical data
-
Molecular techniques are available that allow biomarkers to be identified in a systematic prospectively driven fashion
-
The long sought after goal where therapeutic choice is guided by an informative biomarker 'code' is now upon us
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
American Cancer Society. Lifetime Risk of Developing or Dying From Cancer [online], (2010).
Yabroff, K. R., Warren, J. L. & Brown, M. L. Costs of cancer care in the USA: a descriptive review. Nat. Clin. Pract. Oncol. 4, 643–656 (2007).
Azorsa, D. O. et al. Synthetic lethal RNAi screening identifies sensitizing targets for gemcitabine therapy in pancreatic cancer. J. Transl. Med. 7, 43 (2009).
Schilsky, R. L. Personalized medicine in oncology: the future is now. Nat. Rev. Drug Discov. 9, 363–366 (2010).
Fine, B. M. & Amler, L. Predictive biomarkers in the development of oncology drugs: a therapeutic industry perspective. Clin. Pharmacol. Ther. 85, 535–538 (2009).
Duffy, M. J. & Crown, J. A personalized approach to cancer treatment: how biomarkers can help. Clin. Chem. 54, 1770–1779 (2008).
Park, J. W. et al. Rationale for biomarkers and surrogate end points in mechanism-driven oncology drug development. Clin. Cancer Res. 10, 3885–3896 (2004).
Cronin, M. et al. Analytical validation of the Oncotype DX genomic diagnostic test for recurrence prognosis and therapeutic response prediction in node-negative, estrogen receptor-positive breast cancer. Clin. Chem. 53, 1084–1091 (2007).
Ward, D. G. et al. Identification of serum biomarkers for colon cancer by proteomic analysis. Br. J. Cancer 94, 1898–1905 (2006).
Sarker, D. & Workman, P. Pharmacodynamic biomarkers for molecular cancer therapeutics. Adv. Cancer Res. 96, 213–268 (2007).
Ratain, M. J., Schilsky, R. L., Conley, B. A. & Egorin, M. J. Pharmacodynamics in cancer therapy. J. Clin. Oncol. 8, 1739–1753 (1990).
August, J. Market watch: emerging companion diagnostics for cancer drugs. Nat. Rev. Drug Discov. 9, 351 (2010).
Sawyers, C. Targeted cancer therapy. Nature 432, 294–297 (2004).
Segal, N. H. & Saltz, L. B. Evolving treatment of advanced colon cancer. Annu. Rev. Med. 60, 207–219 (2009).
Badgwell, B. D. et al. Management of bevacizumab-associated bowel perforation: a case series and review of the literature. Ann. Oncol. 19, 577–582 (2008).
Goodsaid, F. & Papaluca, M. Evolution of biomarker qualification at the health authorities. Nat. Biotechnol. 28, 441–443 (2010).
Raftery, J. NICE and the challenge of cancer drugs. BMJ 338, b67 (2009).
Berns, K. et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12, 395–402 (2007).
Slamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182 (1987).
Dawood, S. et al. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J. Clin. Oncol. 28, 92–98 (2010).
Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).
Hudis, C. A. Trastuzumab–mechanism of action and use in clinical practice. N. Engl. J. Med. 357, 39–51 (2007).
Bange, J., Zwick, E. & Ullrich, E. Molecular targets for breast cancer therapy and prevention. Nat. Med. 7, 548–552 (2001).
Romond, E. H. et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 353, 1673–1684 (2005).
Piccart-Gebhart, M. J. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353, 1659–1672 (2005).
Valabrega, G., Montemurro, F. & Aglietta, M. Trastuzumab: mechanism of action, resistance and future perspectives in HER2-overexpressing breast cancer. Ann. Oncol. 18, 977–984 (2007).
Suter, T. M. et al. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J. Clin. Oncol. 25, 3859–3865 (2007).
Muthuswamy, S. K. Trastuzumab resistance: all roads lead to SRC. Nat. Med. 17, 416–418 (2011).
Allison, M. The HER2 testing conundrum. Nat. Biotechnol. 28, 117–119 (2010).
Phillips, K. A. et al. Clinical practice patterns and cost effectiveness of human epidermal growth receptor 2 testing strategies in breast cancer patients. Cancer 115, 5166–5174 (2009).
Cuadros, M. & Villegas, M. Systematic review of HER2 breast cancer testing. Appl. Immunohistochem. Mol. Morphol. 17, 1–7 (2009).
Perez, E. A. et al. HER2 testing in patients with breast cancer: poor correlation between weak positivity by immunohistochemistry and gene amplification by fluorescence in situ hybridization. Mayo Clin. Proc. 77, 148–154 (2002).
Stone, R. M. Optimizing treatment of chronic myeloid leukemia: a rational approach. Oncologist 9, 259–270 (2004).
Deininger, M. W. & Druker, B. J. Specific targeted therapy of chronic myelogenous leukemia with imatinib. Pharmacol. Rev. 55, 401–423 (2003).
Wodarz, D. Heterogeneity in chronic myeloid leukaemia dynamics during imatinib treatment: role of immune responses. Proc. Biol. Sci. 277, 1875–1880 (2010).
Goozner, M. Drug developers unveil strategies aimed at imatinib-resistant CML. J. Natl Cancer Inst. 102, 593–595 (2010).
Breccia, M. Hematology: Nilotinib and dasatinib–new 'magic bullets' for CML? Nat. Rev. Clin. Oncol. 7, 557–558 (2010).
Fuerst, M. L. FDA approves dasatinib for imatinib resistance and intolerance 3 weeks after enthusiastic recommendation from ODAC. Oncol. Times 28, 9–10 (2006).
Kantarjian, H. et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 362, 2260–2270 (2010).
Breccia, M. & Alimena, G. Nilotinib: a second-generation tyrosine kinase inhibitor for chronic myeloid leukemia. Leuk. Res. 34, 129–134 (2010).
Kantarjian, H. et al. Dasatinib. Nat. Rev. Drug Discov. 5, 717–718 (2006).
Sawyers, C. L. Chronic myeloid leukemia. N. Engl. J. Med. 340, 1330–1340 (1999).
Harris, T. Gene and drug matrix for personalized cancer therapy. Nat. Rev. Drug Discov. 9, 660 (2010).
Weisberg, E., Manley, P. W., Cowan-Jacob, S. W., Hochhaus, A. & Griffin, J. D. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat. Rev. Cancer 7, 345–356 (2007).
Terasawa, T., Dahabreh, I. & Trikalinos, T. A. BCR-ABL mutation testing to predict response to tyrosine kinase inhibitors in patients with chronic myeloid leukemia. PLoS Curr. 2, RRN1204 (2010).
Papadopoulos, N., Kinzler, K. W. & Vogelstein, B. The role of companion diagnostics in the development and use of mutation-targeted cancer therapies. Nat. Biotechnol. 24, 985–995 (2006).
Siddiqui, M. A. & Scott, L. J. Imatinib: a review of its use in the management of gastrointestinal stromal tumours. Drugs 67, 805–820 (2007).
Heinrich, M. C. Imatinib treatment of metastatic GIST: don't stop (believing). Lancet Oncol. 11, 910–911 (2010).
Heinrich, M. C. et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J. Clin. Oncol. 21, 4342–4349 (2003).
Ciardiello, F. & Tortora, G. EGFR antagonists in cancer treatment. N. Engl. J. Med. 358, 1160–1174 (2008).
Saltz, L. B. et al. Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J. Clin. Oncol. 22, 1201–1208 (2004).
Lenz, H. J. et al. Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J. Clin. Oncol. 24, 4914–4921 (2006).
Santini, D. Molecular predictive factors of response to anti-EGFR antibodies in colorectal cancer patients. Eur. J. Cancer Suppl. 6, 86–90 (2008).
Saif, M. W. Colorectal cancer in review: the role of the EGFR pathway. Expert Opin. Investig. Drugs 19, 357–369 (2010).
Lièvre, A., Blons, H. & Laurent-Puig, P. Oncogenic mutations as predictive factors in colorectal cancer. Oncogene 29, 3033–3043 (2010).
Linardou, H. et al. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol. 9, 962–972 (2008).
Karapetis, C. S. et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 359, 1757–1765 (2008).
Shankaran, V., Obel, J. & Benson, A. B. 3rd. Predicting response to EGFR inhibitors in metastatic colorectal cancer: current practice and future directions. Oncologist 15, 157–167 (2010).
Mack, G. S. FDA holds court on post hoc data linking KRAS status to drug response. Nat. Biotechnol. 27, 110–112 (2009).
Wolff, A. C. et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J. Clin. Oncol. 25, 118–145 (2007).
Gridelli, C. et al. Erlotinib in non-small cell lung cancer treatment: current status and future development. Oncologist 12, 840–849 (2007).
Oxnard, G. R. & Miller, V. A. Use of erlotinib or gefitinib as initial therapy in advanced NSCLC. Oncology (Williston Park) 24, 392–399 (2010).
Saijo, N. Targeted therapies: Tyrosine-kinase inhibitors–new standard for NSCLC therapy. Nat. Rev. Clin. Oncol. 7, 618–619 (2010).
Maemondo, M. et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362, 2380–2388 (2010).
Mitsudomi, T. et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 11, 121–128 (2010).
Lopez-Chavez, A. & Giaccone, G. Targeted therapies: Importance of patient selection for EGFR TKIs in lung cancer. Nat. Rev. Clin. Oncol. 7, 360–362 (2010).
Massarelli, E. et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin. Cancer Res. 13, 2890–2896 (2007).
Sasaki, T., Rodig, S. J., Chirieac, L. R. & Jänne, P. A. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur. J. Cancer 46, 1773–1780 (2010).
Butrynski, J. E. et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N. Engl. J. Med. 363, 1727–1733 (2010).
De Witt Hamer, P. C. Small molecule kinase inhibitors in glioblastoma: a systematic review of clinical studies. Neuro. Oncol. 12, 304–316 (2010).
Mellinghoff, I. K., Cloughesy, T. F. & Mischel, P. S. PTEN-mediated resistance to epidermal growth factor receptor kinase inhibitors. Clin. Cancer Res. 13, 378–381 (2007).
Mellinghoff, I. K. et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N. Engl. J. Med. 353, 2012–2024 (2005).
Diverio, D., Riccioni, R., Mandelli, F. & Lo Coco, F. The PML/RAR alpha fusion gene in the diagnosis and monitoring of acute promyelocytic leukemia. Haematologica 80, 155–160 (1995).
Soprano, D. R., Qin, P. & Soprano, K. J. Retinoic acid receptors and cancers. Annu. Rev. Nutr. 24, 201–221 (2004).
Lin, R. J. & Evans, R. M. Acquisition of oncogenic potential by RAR chimeras in acute promyelocytic leukemia through formation of homodimers. Mol. Cell 5, 821–830 (2000).
Freemantle, S. J., Spinella, M. J. & Dmitrovsky, E. Retinoids in cancer therapy and chemoprevention: promise meets resistance. Oncogene 22, 7305–7315 (2003).
Zhou, D. C. et al. Frequent mutations in the ligand-binding domain of PML-RARalpha after multiple relapses of acute promyelocytic leukemia: analysis for functional relationship to response to all-trans retinoic acid and histone deacetylase inhibitors in vitro and in vivo. Blood 99, 1356–1363 (2002).
Tang, X. H. & Gudas, L. J. Retinoids, retinoic acid receptors, and cancer. Annu. Rev. Pathol. 6, 345–364 (2011).
Kuendgen, A. et al. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer 106, 112–119 (2006).
De los Santos, M., Zambrano, A., Sánchez-Pacheco, A. & Aranda, A. Histone deacetylase inhibitors regulate retinoic acid receptor beta expression in neuroblastoma cells by both transcriptional and posttranscriptional mechanisms. Mol. Endocrinol. 21, 2416–2426 (2007).
Wooster, R. & Weber, B. L. Breast and ovarian cancer. N. Engl. J. Med. 348, 2339–2347 (2003).
Kaelin, W. G. Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 5, 689–698 (2005).
Ashworth, A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J. Clin. Oncol. 26, 3785–3790 (2008).
Amé, J. C., Spenlehauer, C. & de Murcia, G. The PARP superfamily. Bioessays 26, 882–893 (2004).
Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).
Yap, T. A. et al. First in human phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of KU-0059436 (Ku), a small molecule inhibitor of poly ADP-ribose polymerase (PARP) in cancer patients (p), including BRCA1/2 mutation carriers [abstract]. J. Clin. Oncol. 25 (Suppl.), a3529 (2007).
Ratnam, K. & Low, J. A. Current development of clinical inhibitors of poly(ADP-ribose) polymerase in oncology. Clin. Cancer Res. 13, 1383–1388 (2007).
Foulkes, W. D., Smith, I. E. & Rein-Filho, J. S. Triple-negative breast cancer. N. Engl. J. Med. 363, 1938–1948 (2010).
O'Shaughnessy, J. et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N. Engl. J. Med. 364, 205–214 (2011).
Bath, C. Phase III results for PARP inhibitor iniparib quell optimism about new option for triple-negative metastatic breast cancer. The Asco Post [online], (2011).
Hutchinson, L. Targeted therapies: PARP inhibitor olaparib is safe and effective in patients with BRCA1 and BRCA2 mutations. Nat. Rev. Clin. Oncol. 7, 549 (2010).
Miller, A. J. & Mihm, M. C. Jr. Melanoma. N. Engl. J. Med. 355, 51–65 (2006).
Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).
Nazarian, R. et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468, 973–977 (2010).
Shi, H., Kong, X., Ribas, A. & Lo, R.S. Combinatorial treatments that overcome PDGFRβ-driven resistance of melanoma cells to V600E B-RAF inhibition. Cancer Res. 71, 5067–5074 (2011).
Mullenders, J. & Bernards, R. Loss-of-function genetic screens as a tool to improve the diagnosis and treatment of cancer. Oncogene 28, 4409–4420 (2009).
Cully, M., You, H., Levine, A. J. & Mak, T. W. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat. Rev. Cancer 6, 184–192 (2006).
Iorns, E. et al. Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer. Cancer Cell 13, 91–104 (2008).
Fotheringham, S. et al. Genome-wide loss-of-function screen reveals an important role for the proteasome in HDAC inhibitor-induced apoptosis. Cancer Cell 15, 57–66 (2009).
Khan, O. et al. HR23B is a biomarker for tumor sensitivity to HDAC inhibitor-based therapy. Proc. Natl Acad. Sci. USA 107, 6532–6537 (2010).
Stimson, L., Wood, V., Khan, O., Fotheringham, S. & La Thangue, N. B. HDAC inhibitor-based therapies and haematological malignancy. Ann. Oncol. 20, 1293–1302 (2009).
McConkey, D. Proteasome and HDAC: who's zooming who? Blood 116, 308–309 (2010).
Whitehurst, A. W. et al. Synthetic lethal screen identification of chemosensitizer loci in cancer cells. Nature 446, 815–819 (2007).
Shapiro, C. L. et al. Phase I trial of bortezomib (Velcade™) in combination with paclitaxel in advanced solid tumor patients (pts) [abstract]. J. Clin. Oncol. 23 (Suppl.), a3104 (2005).
Young, R. C. Cancer clinical trials–a chronic but curable crisis. N. Engl. J. Med. 363, 306–309 (2010).
Author information
Authors and Affiliations
Contributions
Both authors researched data for inclusion in the article. N. B. La Thangue contributed to the writing, editing and reviewing the manuscript before submission and during the reviewing process.
Corresponding author
Ethics declarations
Competing interests
N. B. La Thangue is a consultant, stock holder and patent holder for Celleron Therapeutics. D. J. Kerr is a consultant for Celleron Therapeutics.
Rights and permissions
About this article
Cite this article
La Thangue, N., Kerr, D. Predictive biomarkers: a paradigm shift towards personalized cancer medicine. Nat Rev Clin Oncol 8, 587–596 (2011). https://doi.org/10.1038/nrclinonc.2011.121
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrclinonc.2011.121
This article is cited by
-
Perspectives of patients and clinicians on big data and AI in health: a comparative empirical investigation
AI & SOCIETY (2024)
-
Revolutionizing cancer treatment: comprehensive insights into immunotherapeutic strategies
Medical Oncology (2024)
-
A scoping review of statistical methods in studies of biomarker-related treatment heterogeneity for breast cancer
BMC Medical Research Methodology (2023)
-
Circulating and urinary tumour DNA in urothelial carcinoma — upper tract, lower tract and metastatic disease
Nature Reviews Urology (2023)
-
Clonal dynamics limits detection of selection in tumour xenograft CRISPR/Cas9 screens
Cancer Gene Therapy (2023)