Lessons From Considering the Cancer Landscape

May 15, 2013

A number of drugs have been approved that result in significant tumor responses. While many of these new drugs are associated with improved clinical outcomes, much more work in this area is essential, as most patients have tumors without such molecular features.

Carrizosa and colleagues have nicely summarized the major new developments in the use of new targeted agents in the treatment of non–small-cell lung cancer.[1] As outlined, new targets include vascular endothelial growth factor (VEGF) antibodies, epidermal growth factor receptor (EGFR), ALK tyrosine kinase, MET, fibroblast growth factor receptor (FGFR), and other intracellular targets. For newly diagnosed patients who manifest mutations or related features that imply dysregulation of relevant pathways, a number of drugs have been approved that result in significant tumor responses. While many of these new drugs are associated with improved clinical outcomes, much more work in this area is essential, as most patients have tumors without such molecular features. Further, Carrizosa and colleagues describe the need for ongoing evaluation of patients to allow the response of the tumor evolution to be defined from biopsy of tumor tissue, and thereby guide selection of more successful approaches to subsequent tailored therapy. Their review concludes with the concept that further genomic research will identify new targets, but selected clinical trials will need to include provisions to obtain tumor tissue so that the actual behavior-of-cancer mechanism can be defined.[1]

In a recent review, we also advocated for a similar approach, but we more specifically suggested that the use of neoadjuvant, window-of-opportunity trials is a particularly favorable platform for such research.[2] The best example of this approach, reported by Altorki and colleagues involved a 3-week exposure to the oral, dual VEGF kinase–inhibitor pazopanib (Votrient) prior to the resection of early-stage lung cancer.[3] With this neoadjuvant-window study approach, baseline tumor biopsy, quantitative imaging, and serum biomarkers were compared before and after the drug exposure so that the driving molecular mechanism could be inferred more precisely.[3,4]

The basis for such intensive clinical scrutiny of drug effect is highlighted in a recent masterful analysis of the molecular underpinnings of cancer published by Dr. Bert Vogelstein and colleagues.[5] In this review, Vogelstein outlines a synthesis of the current genomic information about the cancer process, reconciled with efforts to exploit this knowledge into successful drug development for clinical practice. Critical points emerge, such as the frequency of mutations. For example, while cancer typically involves two to eight sequential genetic alterations over the period of several decades, the process of aging and exposure to mutagens such as tobacco smoke greatly increase the mutation frequency. Only a small subset of mutations mediates biological consequences that contribute to carcinogenesis. The attributes of such oncogenic mutations are changes resulting in biological modifications that converge on several strategic cellular processes, including regulation of differentiation, control of cell survival, and preservation of genomic integrity. The critical quotation from this article is “that 99.9% of alterations in tumors (including point mutations; copy number alterations; translocations; and epigenetic changes distributed throughout the genome, not just in the coding regions) are immaterial to neoplasia.”[5] The implication of this situation is that vetting the biological significance of such mutational changes is critical in the drug development process.

Another core feature emphasized in the Vogelstein review was the complex and dynamic heterogeneity of the cancer process, which presents another central challenge to drug therapy. The implication of this reality is that successful drug therapy will often mandate the use of drug combinations rather than single-drug therapies, to successfully address cancer heterogeneity. In light of such complexity, the Vogelstein review echoes the recommendation of the Carrizosa article in outlining the need to inform a specific patient’s therapy based on molecular analysis of their actual tumor tissue. This is a critical recommendation, but in clinical practice the opportunity to obtain tumor tissue is often restricted. For that and other reasons, we have recommended pursuing parallel but complementary opportunities to use quantitative tumor imaging to access response to anticancer therapy.[6] This integrated quantitative imaging-molecular analysis approach was used by Altorki in the pazopanib neoadjuvant trial.[3] The Quantitative Biomarker Alliance has been working to standardize this approach to ensure quality and minimize measurement variance in the use of imaging as a quantitative biomarker.[7] In this fashion, quantitative imaging biomarkers of drug response would be developed as robustly as other types of biomarkers, supporting their responsible use in clinical management with validation standards similar to those used for moving genomic information into clinical implementation.[8] This integrated imaging–molecular genomic evaluation approach can help to sort out the salient molecular drivers contributing to tumor regression vs tumor growth.

The Vogelstein review also provides a fuller explanation of the granular complexity of cancer regulatory processes touched upon in the Carrizosa article, such as elaboration on the context-specific actions of particular mutations like KRAS as a function of the nature of how they are modified in the cancer process.[5] In light of such pathway complexity, Vogelstein also proposes other drug-development opportunities, such as understanding the molecular basis of drug metabolism to allow more specific dosing approaches that may mitigate issues with drug cost. He further relates that factors such as understanding critical mechanisms underlying tumor metabolism or how to better design immunotherapies can lead to better therapeutic approaches. However, Vogelstein concludes that while developing greater knowledge of cancer pathways may be the most pressing need of basic cancer research, pragmatically other approaches beyond treating advanced cancer may be prudent. Vogelstein contends that an enhanced focus on implementing early detection and prevention strategies can allow for profound improvements in reducing cancer deaths, while the complexities of tumor biology are elucidated as a second but essential component of a comprehensive approach to overcoming the scourge of cancer.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Carrizosa DR, Mileham KF, Haggstrom DE, et al. New targets and new mechanisms in lung cancer. Oncology (Williston Park). 2013;27:396-408.

2. Mulshine JL, Ondrey FG. Not significant but important. Cancer Prev Res. 2013. In press.

3. Altorki N, Lane ME, Bauer T, et al. Phase II proof-of-concept study of pazopanib monotherapy in treatment-naive patients with stage I/II resectable non-small-cell lung cancer. J Clin Oncol. 2010;28:3131-7.

4. Nikolinakos PG, Altorki N, Yankelevitz D, et al. Plasma cytokine and angiogenic factor profiling identifies markers associated with tumor shrinkage in early-stage non-small cell lung cancer patients treated with pazopanib. Cancer Res. 2010;70:2171-9.

5. Vogelstein B, Papapoulos N, Velculescu VE, et al. Cancer landscapes. Science. 2013;339:1546-58.

6. Mulshine JL, Avila RS, Hirsch FR, Yankelevitz D. Developing CT image-processing tools to accelerate progress in lung cancer drug development. Oncology (Williston Park). 2006;20:1606-14.

7. Buckler, AJ, Mulshine JL, Gottlieb R, et al. The use of volumetric CT as an imaging biomarker in lung cancer. Acad Radiol. 2010;17:100-6.

8. McLeod HL. Cancer pharmacogenomics: early promise but concerted effort needed. Science. 2013;339:1563-6.