Choosing the right patients

Biomarkers that predict the likelihood of response a specific therapy are termed predictive markers. The use of molecular imaging to measure therapeutic targets is an example of a predictive cancer biomarkers^2,9. In clinical practice, predictive assays that measure therapeutic target expression are commonly used to select treatment. An example of a widely used predictive marker is the use of estrogen receptor (ER) expression to direct breast cancer endocrine therapy in breast cancer³. In breast cancers expressing ER, the chance of response to endocrine therapy is as high as 75%, but in the absence of expression, clinical benefit occurs in less than 5% of patients. Molecular imaging can be complementary to tissue-based predictive biomarkers, especially for advanced disease, where imaging offers the ability to assess target expression across all sites of disease and to assess sites challenging to biopsy and assay.

An example of a molecular imaging predictive assay is PET imaging of ER expression using the positron-emitting probe, ¹⁸F-fluoroestradiol (FES). FES uptake correlates with ER expression as measured by a variety of tissue assays^14,15. In early trials, PET found a higher average FES SUV for responder versus non-responders, and low or absent uptake indicated that patients were unlikely to respond to endocrine treatment. As a predictive assay for endocrine therapy, the ability to characterize ER expression over the entire disease burden may offer advantages for patients with for more widespread and refractory disease. FES PET was able to demonstrate the evolution of ER-negative disease in over 30% of patients with endocrine-refractory metastatic breast^6,16, indicating the ability of imaging to direct therapy in advanced disease. These promising early results in single-center trials have spurred the development of multi-center trials to further test the use of FES PET in breast cancer and other diseases.

Choosing the right drug

Molecular imaging can measure drug transport and kinetics through a variety of approaches. Labeled versions of drugs, typically labeled with ¹¹C or ¹⁸F can measure dynamic drug biodistribution and provide key insights in drug clearance and transport to the site of disease. While powerful, this approach requires considerable labor to label and validate drugs labeled with a short-lived positron emitter. An alternative approach is to label a surrogate marker for drug properties-for example, drug transport- that can be used for classes of drugs. An example is ¹¹C-verapmil to measure transport of the efflux protein, P-glycoprotein (p-gp)¹⁷. This approach has been successfully used to demonstrate the impact of a p-gp inhibitor on drug transport across the blood-brain-barrier¹⁸. Imaging drugs can also be used to demonstrate the ability of a drug to reach the target in sufficient quantity to carry out its desired action. For example, studies have shown that that FES PET performed before and after the administration of ER-blocking drugs such as tamoxifen and fulvestrant in breast cancer can help guide drug dosing and reveal patient-to-patient variability in drug penetrance^19,20.

Getting the right result

The standard clinical approach to the assessment of response in cancer patients undergoing treatment for advanced disease is measurement of the size of the tumor typically every two months (usual range: 6 weeks to 3 months) using standard anatomic imaging with CT or MRI²¹. This allows enough time for a tumor to shrink in responding patients or to grow in those with progressive disease. Size-based methods are widely used for response assessment but may not be well suited as early-response indicators. Biochemical and molecular changes will typically precede subsequent changes in tumor size and can provide a much better indictor of whether or not the drug has an effect on the tumor. This principal underlies considerable research and future promise for molecular imaging as an early response indicator. A number of approaches to molecular imaging early response markers have been developed and tested. The most successful thus far have targeted biologic processes that relatively are ubiquitously affected by successful treatment, including processes such as glycolysis and cellular proliferation.

FDG PET has been shown to be a good predictor of early response for a number of several cancers and treatment types²². One of the most dramatic examples is the impact of drug such as imatinib and sunitinib on GI stromal tumors, where dramatic declines in FDG uptake are seen within 24 hours of drug administration²³. An early decline in FDG uptake has also been a robust indicator of breast cancer response to HER2-directed therapy, confirmed in the recent Neo-ALTTO study, where serial FDG PET performed in the setting of a randomized drug trial comparing the efficacy of two different HER2-directed regimens indicated that a decline in FDG uptake with treatment was a robust indicator response to combined HER2-targeted therapy/chemotherapy²⁴. Besides FDG, other radiopharmaceuticals applicable to early response have been tested, including tracers of cellular proliferation and cell death. Thus far, cellular proliferation has been the most successful PD marker tested, mostly using labeled thymidine and analogs²⁵. The thymidine analog ¹⁸F-fluorothymidine (FLT) has shown promise in early trials, including studies indicating an ability to demonstrate response to both chemotherapy and targeted agents as early as a single dose of therapy and as early as a few days after treatment^26,27. These studies have prompted several multi-center FLT PET trials, most commonly testing early breast cancer response to chemotherapy in the neo-adjuvant setting. Although results have been somewhat mixed, at least one trial, ACRIN 6688, has indicated an ability of serial FLT PET pre- and one week after chemotherapy to predict pathologic response post-neoadjuvant chemotherapy²⁸.

Predicting Outcome

The earliest studies of molecular imaging to measure cancer response showed it to be quite predictive of established measures of therapeutic outcomes, such as pathologic response²⁹. In vivo molecular cancer properties can provide evidence of residual active tumor post-therapy, yielding incremental information beyond anatomic imaging spredictive of key patient outcomes such as disease-free and overall survival (DFS and OS). The value of FDG PET in predicting survival has been best demonstrated in lymphoma, where the presence of absence of residual FDG uptake post therapy, independent of the presence or absence residual anatomic abnormalities by CT, is a strong predictor of relapse and survival³⁰. FDG PET is widely used in clinical practice for Hodgkin’s and aggressive non-Hodgkin’s lymphomas, and PET has been accepted as a surrogate endpoint and integral marker in lymphoma clinical trials³¹. It is likely that PET molecular imaging could provide a similarly robust endpoint for other cancers, with FDG or other probes of cancer biology.