Tackling Tumor Sampling: Technical Advances May Help Optimize Molecularly Targeted Treatment Strategies

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology Cancer Treatment Centers of America, Eastern Regional Medical Center

It seems that rarely a month goes by these days without the publication of a major study demonstrating the impact of fresh knowledge regarding molecular abnormalities in a particular tumor type.

Further, an increasing number of reports are highlighting very specific changes in potential defects at the molecular level during treatment that may explain an underlying mechanism of resistance as well as possible therapeutic strategies designed to overcome that resistance.

Although these discoveries hold great promise for the future, there is a critical issue that severely limits the gains that theoretically would be made with molecularly targeted therapies in clinical practice today: When it comes to solid tumors, there are challenges in obtaining appropriate tissue samples for genomic analysis. New approaches to surmount these hurdles include “liquid biopsies” of blood-based biomarkers and the application of fine-needle aspiration (FNA) to next-generation sequencing.

This limitation for solid tumors represents a rather striking contrast to the situation in the socalled “liquid” (hematologic) malignancies.¹ It is possible to sample the blood and/or bone marrow relatively frequently and easily in clinical settings involving a hematologic cancer, such as acute and chronic leukemias and multiple myeloma, to determine whether viable cancer cells are present and then subsequently examine the material in vitro for the presence of changes in individual molecular profiles.

Blood Versus Tissue

In solid tumors, researchers have explored the clinical utility of nonhematologic cancer cells present in the blood or bone marrow, particularly focusing on the prognostic significance of such findings in individual patients with these malignancies.^2,3 More recently, investigative efforts have examined the clinical relevance associated with finding and monitoring tumor-specific DNA in circulation.^4,5

However, the clinical utility of this approach will be questionable until it is clearly documented that solid tumor cells or cancer-specific DNA present in the blood or bone marrow not only can be found in the majority of patients with advanced or metastatic malignancies, but also that any molecular findings are relevant to clinical resistance mechanisms and/or “driver” abnormalities that may be targeted by a subsequently administered antineoplastic. At the present time, such efforts remain within the domain of provocative clinical research.

By contrast, knowledge of molecular changes in existing solid tumor masses, particularly those that do not respond to treatment or progress on their current regimen, may have enormous therapeutic implications for future management. As with the hematologic malignancies, information regarding any changes in the molecular profile in a given solid tumor obtained immediately prior to a necessary modification in the treatment plan will almost certainly optimize the chances that the data will be clinically useful.

FNA Sampling

A recent report examining the utility of obtaining tissue for detailed molecular analysis through FNA has provided strong support for the value of this method in the subsequent analysis of genomic changes in a given cancer.⁶ In this study, nextgeneration sequencing was performed on tissue obtained through FNA from 16 patients with lung tumors, including non-small cell and small cell samples as well as both adenocarcinomas and squamous cell malignancies, and on tissue from 23 individuals with pancreatic cancer. In each case, the sample was sufficient for the analysis to be undertaken successfully.

In addition, there was impressive correlation among 20 genetic alterations identified between the results obtained through FNA of a small group of pancreatic cancers with the corresponding tissue obtained at the time of surgical resection of the malignancy.

The ability to successfully perform a detailed molecular evaluation of tissue obtained during a less invasive procedure such as FNA, compared with a requirement for a much larger quantity of malignant material, should substantially enhance the potential for clinicians to determine several lines of antineoplastic therapy (if necessary), based at least in part on unique molecular characteristics present within the individual cancer when the specific treatment programs are initiated. And that could represent a notable advance in the translation of genomic discoveries to clinical practice.

Maurie Markman, MD, editor-in-chief, is senior vice president for Clinical Affairs and national director for Medical Oncology at Cancer Treatment Centers of America. maurie.markman@ctca-hope.com

References

1. Hehlmann R, Muller MC, Lauseker M, et al. Deep molecular response is reached by the majority of patients with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-Study IV [published online December 2, 2013]. J Clin Oncol. 2014;32(5):415-423.
2. Cristofanilli M, Budd GT, Ellis MJ, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351(8):781-791.
3. Gröbe A, Blessmann M, Hanken H, et al. Prognostic relevance of circulating tumor cells in blood and disseminated tumor cells in bone marrow of patients with squamous cell carcinoma of the oral cavity [published online November 11, 2013]. Clin Cancer Res. 2014;20(2):425-433.
4. Dawson SJ, Tsui DW, Murtaza M, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer [published online March 13, 2013]. N Engl J Med. 2013;368(13):1199-1209.
5. . Diaz Jr. LA, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA [published online January 21, 2014]. J Clin Oncol. 2014;32(6):579-586.
6. Young G, Wang K, He J, et al. Clinical next-generation sequencing successfully applied to fine-needle aspirations of pulmonary and pancreatic neoplasms [published online July 24, 2013]. Cancer Cytopathol. 2013;(12)121:688-694.