In patients with suspected MBC, the optimal strategy for detecting osseous metastases is unknown. For example, the National Comprehensive Cancer Network guidelines recommend radiologic evaluation in the setting of clinical suspicion and/or high risk of metastases, but they do not recommend specific imaging modalities.6
Similarly, the American Society of Clinical Oncology guidelines indicate that CT, PET, PET/CT, BSc, and/or magnetic resonance imaging may play a role in evaluating the patient with suspected MBC, but, again, they do not recommend a specific imaging paradigm.6,7
The absence of consensus recommendations in this setting likely reflects, in part, the limitations of the imaging modalities themselves. For example, BSc provides only indirect information about tumor activity, does not detect osteolytic metastases, and poorly detects indolent metastases or metastases to poorly vascularized areas.2
PET (without CT) provides direct information about tumor activity and detects osteolytic metastases but is insensitive to small lesions, poorly detects osteoblastic metastases, and is limited by false positive results with inflammatory processes.2,3,8–10
It is also likely that the absence of consensus recommendations in this setting reflects significant deficiencies in the existing data. For example, several studies have compared the diagnostic performance of BSc and PET (without CT) in detecting breast cancer metastases to bone. However, these studies have been largely limited by modest sample sizes and low rates of gold-standard pathologic correlates.8–14
Studies without pathologic correlates have a significant potential for investigator bias and are complicated by reliance on multiple diagnostic tests with variable sensitivity and specificity. To our knowledge, we report the largest study to date comparing BSc with integrated PET/CT (as opposed to PET alone) for the detection of osseous metastases in women undergoing evaluation for suspected MBC. Furthermore, this study has the largest proportion of pathologic correlates in the published literature to date. Specifically, 28 patients (17%) underwent bone biopsy in our study, which compares favorably to the 6.7% of pathologic correlates in the largest reported series of PET (without CT) versus BSc.10
Almost all patients (93%) who underwent bone biopsy had pathology consistent with breast cancer to bone. Moreover 12 (29%) of the 31 patients with discordant PET/CT and BSc results underwent bone biopsy/FNA, and osseous metastases were confirmed in all occurrences.
In our study, the observed concordance between PET/CT and BSc was not only high (81%) but also superior to reported concordance between BSc (or other conventional imaging techniques) and PET (without CT) in several comparable studies.8,9,13
Thus, these data suggest that PET/CT and BSc provide largely redundant information about the presence or absence of osseous metastases in the majority of instances for which MBC is suspected. However, PET/CT confers the additional advantage of identifying nonosseous metastases, thereby potentially obviating the need for additional imaging. In this study, for example, 62% of patients with positive PET/CT had evidence of nonosseous metastases; of these patients, 6% had equivocal BSc, and 42% had negative BSc.
We did not include data on all patients undergoing either only a PET/CT or a BSc for suspected MBC; rather, we sought to correlate results from patients undergoing both imaging modalities. Additionally, because PET/CT has not routinely been performed at MSKCC on all patients with suspected MBC but has mainly been used in instances of diagnostic uncertainty, our cohort is likely enriched for such occurrences. Given that our occurrences may have represented those with higher degrees of clinician uncertainty, it is worth noting that osseous metastases were detected on biopsy in nine patients, and the metastases were seen on PET/CT and not BSc, whereas correlative clinical and radiologic findings in the two patients with positive BSc and negative PET/CT suggest that these were, in fact, true negatives on PET/CT. In these instances, the combined anatomic and functional imaging of PET/CT may have lowered the rate of false negatives, possibly by detecting osteoblastic metastases on CT. However, it should be noted that the anatomic images obtained with PET/CT have historically been less detailed than those obtained with dedicated CT, as demonstrated by one of our patients, for whom bone metastases from invasive lobular carcinoma were seen subsequently on CT. This patient represents a subgroup of breast cancer associated with strong expression of estrogen and progesterone receptors, which tends to be less metabolically active and thus leads to potentially lower standard uptake values on PET.15
Therefore, this may be a subgroup in whom PET/CT should be used cautiously.
An additional theoretical disadvantage of PET/CT compared with BSc is that limited views of the long bones are obtained. However, isolated breast cancer metastases to the distal skeleton are extremely rare; whether this represents a clinically relevant limitation for PET/CT is unknown. Although BSc allows imaging of the entire skeleton, use is currently being curtailed by an impending shortage of technetium. Therefore, there is a need to explore other tracers, such as fluorine-18-fluoride, which can be detected on PET/CT and may be more sensitive for osseous metastases than BSc with Tc-99m MDP.16
The limitation of fluorine-18-fluoride compared with FDG is that visceral metastases do not accumulate the tracer. Other radiotracers, such as isotopes of gallium and copper, have been bound to monoclonal antibodies, and the resultant conjugate can be detected on PET/CT.17
These novel approaches may have a future role in imaging patients with subgroups of breast cancer, such as tumors that overexpress the human epidermal growth factor receptor 2.18–20
Notably, our study was limited to patients with suspected MBC and did not include women undergoing surveillance after an early-stage or locally advanced breast cancer diagnosis. Although it is unknown whether early confirmation of MBC in women undergoing evaluation for suspected MBC translates into improved patient-specific outcomes, efficiency in the accurate confirmation of MBC is clinically useful in all settings. Timely and efficient evaluation of suspected MBC with a single test read by a single, experienced radiologist could reduce patient (and physician) anxiety in confirming or refuting the diagnosis, decrease the need for additional radiologic testing, minimize the time spent by clinicians in distilling discordant reports from different tests reported by different radiologists (often working at different imaging centers and without access to prior imaging), prevent unnecessary delays in therapy initiation, and likely improve patient quality of life. Timely institution of bisphosphonate therapy when MBC to bone is confirmed might also potentially decrease the early risk of skeletal-related events. In addition, because the gold standard for confirming MBC(ie, bone biopsy/FNA) is not universally recommended and/or available, a single study conferring both anatomic and metabolic information with high bone biopsy concordance, as demonstrated in our study, can increase clinician confidence in initiating palliative therapy. Furthermore, it is possible that an efficient, single-study strategy with integrated PET/CT is ultimately cost effective compared with conventional strategies; however, a formal analysis is warranted.
In conclusion, our study represents, to our knowledge, the largest experience comparing integrated PET/CT and BSc for the diagnosis of osseous metastases from suspected MBC and the largest series to evaluate PET/CT with pathologic correlates. We have demonstrated a high degree of concordance between these imaging modalities, which suggests redundancy for detecting osseous metastases with both modalities. Furthermore, these results suggest that PET/CT may be superior in evaluating women with suspected MBC, as evidenced by the high rate of pathologically confirmed osseous metastases in women with positive PET/CT and negative BSc results. PET/CT also detected nonosseous metastases in 62% of patients with positive PET/CT in our study. Consequently, BSc may potentially be avoided in most patients undergoing PET/CT for suspected skeletal metastases. These results indicate that a prospectively conducted study evaluating the sensitivity and specificity of PET/CT in women with suspected MBC is warranted.