Breast Cancer: When Molecular Imaging is the Right Choice
Molecular imaging technology—specifically whole-body FDG-PET and PET/CT—has long been involved in guiding breast cancer treatment decisions. In fact, staging of breast cancer with FDG-PET has been approved by CMS for reimbursement for quite some time. Today, whole-body PET and PET/CT are fairly widely used and accepted in the staging and clinical management of breast cancer. However, there is currently no uniform clinical utilization of PET and PET/CT in breast cancer. Firm practice guidelines do not exist. In some cases, the technology might be over-used—but more frequently—utilization is much too low.

As diagnostic imaging and treatment options expand, the role of PET is expected to change. David Mankoff, MD, PhD, an associate professor of radiology at the University of Washington School of Medicine in Seattle is a leading expert in the use of state-of-the-art imaging to better diagnose cancer and guide treatment decisions. He explains the promise of PET in breast cancer staging and management. Dr. Mankoff also outlines a few pitfalls for practices to avoid.

PET: The right information at the right time

FDG-PET is the only form of molecular imaging currently used in breast cancer cases. Oncologists turn to PET to provide information for a number of indications, including staging, monitoring therapeutic response, and increasingly, to direct therapy, says Mankoff. “FDG-PET is extremely useful in staging advanced breast cancer and monitoring systemic response to therapy,” he continues. However, FDG-PET is not necessarily the right imaging study for all breast cancer patients. That is, not all breast cancers benefit from PET. PET’s utility hinges on the patient’s stage and the clinical questions asked.

PET provides critical clinical data when used in staging recurrent or metastatic breast cancer and locally advanced breast cancer. Specifically, the modality can provide useful information about whether or not the cancer has spread to the lymph nodes and more distant sites. Another area where PET could play a pivotal role, says Mankoff, is monitoring response to therapy, especially in metastatic disease and bone-dominant metastatic breast cancer. In fact, PET may be currently under-utilized in metastatic cases. Traditionally, some referring oncologists avoided applying advanced imaging approaches to metastatic breast cancer because it is viewed as incurable. The definition of incurable, however, has evolved in the last decade, largely due to an increasing array of choices for systemic therapy of breast cancer, making PET an increasingly useful imaging tool in metastatic disease.

“Patients with bone-dominant metastatic breast cancer can live many years after diagnosis, primarily due to the availability of improved therapeutic options,” Mankoff says. As the number of therapeutic options for metastatic breast cancer continues to grow, it becomes more important to determine whether or not a patient is responding to a specific therapy. “It’s a very important application for PET and PET/CT because other modalities can not always provide the necessary information to inform decisions about therapeutic response,” says Mankoff.  “This is especially true in bone-dominant breast cancer.”

The flip side: Over-utilization?

“There are a few cases where some centers may use PET, even though it is unlikely to be helpful,” Mankoff says. Whole-body PET has not been shown to be useful in early stage breast cancer cases, particularly newly diagnosed stage 1 or early stage 2 patients. Oncologists may order a PET scan to determine if the cancer has spread to the lymph nodes. “Some practices may order a PET scan just to see if there is any evidence of spread, sometimes to allay patients’ fears,” says Mankoff.

But PET is not likely to be useful in newly diagnosed, early stage breast cancer.  PET is not sufficiently sensitive for detecting an early cancer spread to axillary nodes compared to the current standard of care: sentinel lymph node mapping. “Studies comparing PET to sentinel lymph node mapping show that PET’s sensitivity can be as low as 20 to 40 percent. In other words, it misses 60 to 80 percent of nodal metastases in early breast cancer,” Mankoff points out. In addition, there is some potential for false positives on an early stage PET scan. “In these cases, PET has not been shown to be helpful or cost-effective,” he says. Sites that turn to PET in early-stage disease to address patient anxiety paradoxically risk increasing patient anxiety and delaying care if false findings occur.

There is a related area where some centers may fall into the inappropriate use trap. In addition to axillary nodal staging, some centers may order a PET study for systemic staging of early breast cancer to determine if the disease has spread to distant sites. The problem, says Mankoff is two-fold. The spread to distant sites in early disease, especially in the absence of axillary modal spread, is rare. PET has not been widely studied for systemic staging for early-stage breast cancer; however, prior studies using other staging modalities such as CT and bone scan have not favored systemic staging for early disease, especially in the absence of axillary spread. “Some of the studies of systemic staging of early breast cancer report up to five or six false positives for every true positive,” Mankoff says. “Therefore, in the absence of symptoms, systemic staging is not recommended for early breast cancer. There is no reason to think findings would differ for FDG PET/CT, at least not in the absence of supporting data.”

The upshot? PET is unlikely to provide helpful information in detecting regional spread to the lymph modes or metastatic spread beyond the axilla in early-stage disease. There are, however, circumstances where PET is useful in detecting regional spread to the lymph nodes in recurring or advanced breast cancer. “What’s needed are more studies and more education about instances in which PET is inappropriate and not helpful,” concludes Mankoff. One recent source for information is The National Comprehensive Cancer Network; the organization publishes guidelines to help inform decision-making in the management of all types of cancer.

Changing patient management, changing outcomes

Clinical research shows PET can change management and outcomes in breast cancer. Over the last five years, numerous studies have shown that PET changes management in up to 40 percent of breast cancer cases. In some cases, PET may provide the data needed to shift radiation fields. In others, it may show that a patient is not responding to a specific therapy, and an alterative can be offered.

“FDG-PET is most likely to impact the management and treatment of breast cancer when the referring oncologist asks specific questions,” explains Mankoff. For example, when an oncologist orders a PET study to determine if the extent of disease is locoregional or more widespread, PET may have a significant impact upon the choice of therapy. 

Emerging applications

PET has demonstrated its merit in many breast cancer applications, but the technology could be used more widely in several ways. For instance, the emergence of new treatments for breast cancer presents new opportunities. In addition, new radiotracers also could boost the utility of PET in breast cancer. Finally, positron emission mammography (PEM), a new PET technology, could improve early-stage imaging

In the past, oncologists were fairly limited in their treatment choices for patients with breast cancer. The last few years, however, have seen the addition of a number of new therapeutic options. “With more treatment options, oncologists need to know very quickly if they have selected the right one because the patient can be switched to an alternative that may be more effective,” says Mankoff. Measuring early response to therapy is the domain of PET imaging.

The second emerging arena is radio-tracer development. Several new tracers under development could deliver additional improvements in PET imaging for breast cancer. For example, proliferation tracers such as 18F-fluorothymidine (FLT) can be used to evaluate cell proliferation to provide additional information about early therapeutic response. Early research indicates that FLT may indicate response to treatment even earlier than FDG. FES, a labeled estrogen, can be used for estrogen-receptor imaging to predict which cancers will respond to or resist hormonal therapy. In addition, FES could be deployed to assess the effectiveness of treatments that target estrogen.

PEM, a dedicated imaging device for the breast, is designed for positron imaging in the breast and offers the potential for higher spatial resolution and the ability to quantify tracer uptake in small breast lesions. In the future, PEM may be used in early staging of breast cancer and to help direct early breast cancer treatment using FDG or other tracers.

The big picture: reimbursement and regulation

CMS approved breast cancer staging as one of the first indications for PET scanning five years ago, and reimbursement remains relatively favorable with CMS paying fairly broadly for staging and re-staging of breast cancer as well as monitoring therapeutic response. There are exceptions to CMS’ reimbursement policy. Axillary node staging of early breast cancer, for example, is not covered; however, data have not yet shown that PET provides useful information when used to stage these cases.

On the regulation side, breast cancer is an area where PET and molecular imaging can play a significant role; it will be important for regulatory approaches to be tailored to molecular imaging applications.  Mankoff explains, “Regulatory agencies need to streamline the path to clinical use for diagnostic agents. They should not be treated in the same was as therapeutic agents. Tracers differ from therapeutic agents in a number of ways. Physicians do not give patients diagnostic agents over and over again, and the diagnostic agents do not have any pharmacological effects. I suspect the regulatory issues associated with new imaging probes will be faced first in the PET arena, as new PET tracers are farther along in the development process than other molecular imaging modality agents.” The Society of Nuclear Medicine (SNM) and other molecular imaging organizations aim to resolve the issue by educating regulatory bodies about the nuances of diagnostic agents used in molecular imaging studies.

PET delivers

PET continues to prove its utility in breast cancer. For years, molecular imaging’s premiere modality has shown that it can accurately stage advanced and locally advanced breast cancer. Increasingly, medical oncologists turn to PET as the imaging tool to monitor therapeutic response and to direct therapy. In the rapidly evolving world of breast cancer treatment, PET provides a means to gather the clinically useful data needed to inform treatment options. PET is still in its early stages of utilization. New developments in the form of new tracers will further enhance the utility of PET to the benefit of breast cancer patients.

PET•CT study shows large primary tumor with axillary lymph node metastases. Biograph 16 PET•CT images courtesy of Bejing Hospital, Beijing, China.