Molecular Imaging Brings Precision Oncology Closer to Clinic

Pam Harrison

September 22, 2016

Novel molecular imaging agents, along with refinements in more traditional imaging technologies, are poised to advance the development of new targeted therapies that could bring personalized oncology to the fore, an overview of the latest imaging biomarkers suggests.

The review article was published online September 7 in Science Translational Medicine.

However, barriers to the development of imagining biomarkers, including financial incentives for industry to pursue their development, along with reimbursement for the tests themselves, need to be overcome before precision oncology becomes a reality, researchers caution.

The new imaging biomarkers that the authors discuss "would be of great value in planning targeted/personalized therapy if it can be demonstrated that they are both accurate and efficacious," John Mendelsohn, MD, director, Khalifa Institute for Personalized Cancer Therapy, MD Anderson Cancer Center, Houston, Texas, told Medscape Medical News. He was not involved in the review and was approached for comment.

"While the cost of imaging is high, the cost of targeted therapies is much higher, so selecting patients who are more likely to benefit from a particular targeted therapy will be very helpful both for the patient and for the country's healthcare bill," Dr Mendelsohn added.

Predicting Treatment Response

In the review, lead author Ralph Weissleder, MD, PhD, Massachusetts General Hospital, Boston, and multicenter colleagues explain that "precision oncology aims to adapt treatment decisions to an individual tumor's molecular and genetic characteristics, thereby increasing the chance of a successful outcome."

By bringing together both imaging and other biomarker data, "we now have the opportunity to determine whether a given therapy will lead to a response in a patient and whether the patient is receiving the optimal dose," they add.

One such example of a clinical imaging probe that will enable oncologic precision medicine is the glucose analog 2-deoxy-2 [18F] fluoro-D-glucose (18F-FDG).

Early declines in metabolic activity detected by 18F-FDG can tell practitioners whether patients will be sensitive to chemotherapy before treatment is initiated, the authors point out.

Being able to anticipate whether a given patient will respond to treatment early on in the course of therapy is especially important given the high costs of many oncologic agents in use today, they add. Another example of an imaging-based predictive biomarker is [18F] fluoroestradiol (18F-FES).

Already in use clinically, 18F-FES positron emission tomography (PET)–computed tomography (CT) can assess whether treatment with the estrogen receptor (ER) antagonist fulvestrant binds to estrogen receptors in patients with estrogen-positive breast cancer and what dose is needed to obliterate estrogen receptors.

"Similar work has been successfully applied to the ER antagonist and the ER degrader GDC-0810 ([developed by] Genentech)," the authors add.

Yet another example is that of the imaging pharmacodynamic biomarker, 18F-fluorodihydrotestosterone (FDHT), which has again been used to assess optimal drug concentrations of apalutamide (ARN-509, Aragon Pharmaceuticals) for the treatment of castration-resistant prostate cancer.

The dose of apalutamide determined by uptake of FDHT and subsequently accepted by the US Food and Drug Administration (FDA) was substantially lower than the dose that would have been determined by standard clinical trial results.

"The combined use of closely related therapeutic and diagnostic molecules ('theranostics') has [now] been explored for different drug classes," Dr. Weissleder and coauthors continue.

Already, SSTR2 177Lu-DOTATATE is well established in the management of neuroendocrine tumors to improve patient outcomes.

By documenting quantitative imaging — in other words by analyzing the intensity and the extent of theranostic expression — practitioners can adjust the dose of a given agent on a patient-to-patient basis.

Encouraging clinical results are also being reported for a theranostic agent targeting prostate-specific membrane antigen (PSMA) in men with metastatic prostate cancer. 68Ga-PSMA-PET imaging has been shown to increase detection of metastatic sites, even at low serum prostatic specific antigen values, as the authors point out.

"These tailored approaches are quite attractive and have spurred the development of more advanced targeted agents," they observe: PEN-221 (Tarveda Therapeutics) comes to mind in this regard.

Three Agents Already Approved

Encouragingly, three new molecular imaging agents — all developed by academia — have been approved by the FDA since 2012, two of them very recently.

Discouragingly, it took far too long for these agents to reach the clinic where they could be practically applied, the authors comment.

For example, C-choline for prostate cancer, developed largely by the Mayo Clinic, took over 15 years to reach the clinic.

A similar time course was seen with the somatostatin receptor ligand 68Ga-DOTATATE for PET imaging, while the development of 18F fluciclovine  to image prostate cancer took approximately 8 years to achieve its clinical endpoint.

High-Quality Biopsies

Before any imaging can be done, practitioners need to acquire high-quality biopsy samples so that they can be analyzed for mutations and help match a targeted agent to its genetic characteristics.

"A recent trend in image-guided biopsies has been to collect more than the typical one to two cores necessary for the traditional diagnostic pathology workup," Dr Weisslender and coauthors observe.

Today, coaxial systems allow operators to do exactly that, as biopsy needles quickly collect repeat tissues samples under image guidance, providing operators with enough tissue to permit multiple types of testing, including genotyping, he adds.

Newer analytical techniques also make it possible to perform multiple analyses on fewer cells, meaning patients are subject to less invasive procedures and fewer complications.

Because current pathological and molecular analyses of tumor specimens are fixed in time, current approaches cannot track any changes in tumor morphology or mutations over time.

To address this, operators now have access to whole-body PET-CT scans that can hone in on multiple metastatic sites and identify patients more likely to respond to targeted therapy, the authors say.

There is also the possibility that operators can resort to quantitative feature analysis of data sets obtained on CT or MRI to identify molecular tumor phenotypes.

By enhancing patient selection, molecular imaging could also help reduce the number of patients needed in early-stage clinical trials, as the authors also note.

"The tools we have now for managing patients are improved over what they once were, but they are certainly not optimal," Dr Mendelsohn conceded.

"So the whole point of the article is that imaging offers the potential to improve diagnostic capabilities and I think physicians will embrace any new approach that enhances their ability to treat patients more effectively and that are cost-effective, once efficacy has been demonstrated," he added.

Dr Weisslender has disclosed no relevant financial relationships.  Dr Mendelsohn reports that he is on the board of Merrimack Pharmaceuticals.

Sci Transl Med. Published online September 7, 2016. Abstract

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