Clinical Utility of 18F-FDG PET/CT in Staging Localized Breast Cancer Before Initiating Preoperative Systemic Therapy (2024)

Background

Breast cancer is the most common cancer and the second leading cause of cancer mortality in women in the United States and globally, with approximately 270,000 women diagnosed in 2019 and >40,000 breast cancer–related deaths in the United States. The disease is localized to the breast in 62% of patients and to the breast and regional nodes in 30%.¹ Primary preoperative systemic therapy (PST) is commonly used in patients with localized disease with a larger primary tumor or regionally advanced disease; it results in the downstaging of breast and regional nodal disease burden and facilitates breast conservation and/or less extensive axillary surgery.² Upstaging to a higher regional stage or detection of metastatic disease may impact prognosis and management. Therefore, accurate staging of breast cancer is critical in prognostication and guiding local and systemic treatments and their optimal sequencing.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer recommend CT of the chest, abdomen, and pelvis with contrast and bone scan (CTBS) for staging of patients with clinically staged localized breast cancer (cT0–4N1–3 or T2–4N0) who are candidates for PST and who display clinical symptoms based on category 2B evidence.^{3 18}F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT is considered optional in circ*mstances in which CTBS is equivocal or suspicious. Prior studies reported greater sensitivity of PET/CT versus CT of the body for the detection of regional nodal metastases and distant metastases, and greater accuracy versus bone scan in the detection of bone metastases.^4–6 One retrospective study by Niikura et al⁷ reported 97.4% sensitivity and 91.2% specificity for PET/CT imaging compared with 85.9% sensitivity and 67.3% specificity for conventional techniques, including CT, ultrasonography, radiograph, and bone scan, in detecting distant metastases. In regard to upstaging rates, studies have reported that approximately 15% of patients with initial clinical stage ≥IIB breast cancer were upstaged to stage IV breast cancer after systemic staging with PET/CT.^8,9 Similarly, Riedl et al¹⁰ showed that PET/CT revealed unsuspected distant metastases in 17% of patients aged <40 years with clinical stage IIB breast cancer. A recent retrospective study by Yararbas et al¹¹ showed that overall upstaging rates based on identification of extra-axillary regional lymph nodes and distant metastases were 18.6% of patients with initial stage IIA, 30% of those with stage IIB, and 46.3% of those with stage IIIA breast cancer after PET/CT.

Compared with CTBS, PET/CT has several potential advantages for staging that need to be considered, especially in patients who have locally advanced breast cancer and are candidates for PST before surgery who require an efficient and expeditious workup. These include greater patient convenience, reduced procedure time, and imaging with only 1 rather than 2 contrast/tracer injections. In addition, a PET/CT base-of-skull-to-thigh scan has a lower radiation dose than a combination of CTBS, 14 mSv, and 21 mSv, respectively.^12,13 We report the results of a retrospective study evaluating upstaging rates after PET/CT as initial and/or only imaging study in patients with newly diagnosed clinical stage IIA–IIIC breast cancer who received PST before planned surgery, and our institution’s total Medicare reimbursem*nt rates for PET/CT and CTBS.

Methods

Results

Discussion

We have found that approximately 37% of patients with clinical stage IIA–IIIC breast cancer who underwent ¹⁸F-FDG PET/CT before receiving primary PST before planned surgery showed more extensive disease, including 23% with more extensive regional nodal metastases and 14% with distant metastases. These rates are similar to upstaging rates that were previously reported in patients with localized breast cancer who underwent systemic staging with PET/CT.⁴ We also observed that the costs between CTs of the chest, abdomen, and pelvis with CTBS and PET/CT were comparable. Although the sensitivity of PET/CT in this setting seemed ideal, this result should be interpreted with caution because our study was not designed to examine the sensitivity of PET/CT relative to other imaging modalities. Nevertheless, the positive predictive value of 73% for detecting distant metastases supports the clinical utility of PET/CT as a screening tool for distant metastases in this setting, so long as distant recurrence is confirmed by histologic confirmation.

Regional extra-axillary lymph nodes, such as internal mammary, infraclavicular, and supraclavicular nodes (N2 and N3), can be clinically occult. Studies have shown that PET/CT can detect regional nodes with higher sensitivity than conventional imaging procedures such as contrast enhanced CT, ultrasound, or radiograph.^4,5,15 Identification of regional nodal involvement can guide local treatment decisions and their optimal sequencing. Two prospective studies have shown that detection of extra-axillary regional nodal metastases on PET/CT resulted in modification of surgery or extension of radiation treatment fields.^15,16 In the first study, Cochet et al¹⁵ found that the overall upstaging rate from N1 to N3 disease was approximately 20%, which was similar to the rate of 24% found in our study. Krammer et al¹⁶ also showed that a substantial number of patients (57%) with changes in local management had been upstaging from N1 to N3 disease.

In this study, we also found that some patients were downstaged by PET/CT. The highest downstaging frequency occurred in those with initial clinical stage IIIC breast cancer, wherein regional lymph node with N3 disease, identified on breast MRI and axillary ultrasound, was modified to N1 disease. This downstaging effect could result from the low specificity of nonfunctional imaging studies in detecting regional extra-axillary nodes.⁵

Our evaluation of unsuspected distant metastases showed that PET/CT resulted in a detection rate of 13% for those with initial clinical stage IIB disease, and at greater rates of 17% to 37% for those with stage III disease. A prospective study by Groheux et al¹⁷ in 2012 showed that disease-specific survival was significantly shorter for patients found to have unsuspected distant metastases on PET/CT (88% without metastases vs 57% for those with metastases; P<.001). In our study, we observed that patients found to have unsuspected distant metastases on PET/CT received palliative systemic therapy instead of curative PST followed by planned surgery. Therefore, identification of unsuspected distant metastases during clinical staging is essential in prognostication, because it can convert management from curative to palliative intent.

Historically, the triple-negative breast cancer subtype is known for its aggressive behavior and high rates of node positivity, metastatic disease, and early peak of recurrence. It is found more commonly in younger Hispanic women and non-Hispanic black women who carry a mutation in the BRCA1 gene.^18,19 We found no associations between upstaging to stage IV disease and clinical characteristics, including race, tumor histology, and triple-negative receptor phenotype. This finding is also consistent with another study of 232 patients with early triple-negative breast cancer that found no associations between upstaging to stage IV disease and clinical characteristics, including age, race (white vs nonwhite), tumor histology, and tumor grade.⁸

The strengths of this study are the large number of patients evaluated who received PST and the report of Medicare reimbursem*nt cost differences between CT chest, abdomen, and pelvis with CTBS versus PET/CT. Systemic staging scans can be costly; the NCCN Guidelines³ recommend performing them only when indicated based on clinical symptoms in early-stage breast cancer. Although downstream costs were not included in our analysis, Merrill et al²⁰ reported additional downstream costs, including follow-up scan and biopsy of $1,506 per patient, for patients who underwent systemic staging with PET/CT or CTBS when they were not clinically indicated.²⁰

Our study has several limitations. Data were obtained from a single institution retrospectively with potential for inherent selection and interpretation biases, and we did not directly compare PET/CT with CTBS. In addition, histologic confirmation was not available for most patients with metastatic disease found on PET/CT. We also detected 10 false-positives for distant metastases, resulting in PET/CT specificity and a positive predictive value of 94% and 73%, respectively. Therefore, findings of distant metastases on PET/CT required additional histologic biopsy or corroboration with other imaging modalities. Finally, most cases in this study were ductal carcinoma in histology; therefore, the clinical utility of PET/CT in other histologies such as lobular carcinoma cannot be interpreted from this study.

Conclusions

Given the high detection rate, comparable cost, lower radiation dose, and greater patient convenience, PET/CT should be considered as an alternative to CTBS rather than considered as optional when systemic staging is clinically indicated in patients with stage IIA–IIIC breast cancer who require an efficient and expeditious workup before initiating PST prior to planned surgery.