Utilization of ¹⁸F-Fluoroestradiol for Clinical Field Design and Dose Determination in Breast Radiation Therapy

Introduction

Breast cancer is the most common cancer diagnosis in women. Expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) has important prognostic and therapeutic implications, and most breast cancers are ER-positive (ER+).¹ Historically, receptor status has been determined by immunohistochemical staining and fluorescence in situ hybridization of tissue biopsy specimens.¹ However, obtaining an adequate biopsy from all suspicious disease sites is not always safe or feasible, prompting the development of alternative diagnostic staging strategies.

The positron emission tomography (PET) radiotracer ¹⁸F-fluoroestradiol (FES) was approved by the Food and Drug Administration as a radiopharmaceutical for PET imaging to visualize ER expression.² FES-PET imaging was incorporated into the 2025 National Comprehensive Cancer Network guidelines as a consideration for patients with recurrent or metastatic ER+ breast cancer as an adjunct to biopsy.² A meta-analysis showed 78% sensitivity and 98% specificity of FES-PET in detecting nonbreast lesions, using immunohistochemical results as the reference standard.³ FES-PET has a variety of diagnostic uses including identification of a lesion to biopsy, assessment of the burden of ER+ disease, and additional evaluation of fluorodeoxyglucose (FDG) PET-avid findings.² Future applications of FES-PET include radiographic staging of ER+ lobular breast carcinoma, which can be difficult to image with other modalities, because tumor growth is less typically cohesive than invasive ductal carcinoma.⁴ FES-PET may also predict response to ER-targeted therapies⁵ and may be useful in other ER+ malignancies, such as endometrial cancer.⁶

To our knowledge, FES-PET has not been routinely used to assist with radiation therapy (RT) target delineation. This case report highlights the utility of FES-PET in radiation treatment planning in a patient with extensive benign bilateral adenopathy.

Case Presentation

The patient is a 37-year-old woman, G2P1, with a history of surgically repaired congenital atrial septal defect and right breast cancer. The patient presented with right breast pain and right nipple inversion, which prompted a diagnostic mammogram and ultrasonography, revealing a 1.6 cm mass at the 8-o’clock position, 3 cm from the nipple in the right breast and bilateral axillary adenopathy in axillary levels I to III. Pathology from a core biopsy of the right breast mass showed a grade 2, ER+, PR+, HER2-negative, Ki-67 25% infiltrating ductal carcinoma with associated intermediate-grade ductal carcinoma in situ. Fine-needle aspiration (FNA) of a right axillary node showed metastatic adenocarcinoma. FNA of the left axilla showed benign lymphoid tissue.

On presentation to our institution for a second opinion, a repeat diagnostic mammogram showed 11 cm of calcifications extending to skin and pectoralis muscle. Repeat ultrasound showed a hypoechoic mass corresponding to the known primary invasive tumor, measuring 3.4 cm, and the biopsy-proven level I axillary node measured 2.9 cm. There were >10 abnormal level I/II axillary lymph nodes bilaterally, as well as abnormal bilateral level III axillary lymph nodes and suspicious bilateral supraclavicular (SCV) lymphadenopathy. Internal mammary lymph node chains showed no suspicious adenopathy. An FNA of the bilateral SCV nodes was negative for malignancy. Figure 1 shows a radiology diagram of the extent of nodal abnormality, biopsy sites, and pathologically positive disease.

Figure 1.

Radiographic lymphadenopathy. Coronal view of a computed tomography scan showing extensive (A) ipsilateral right and contralateral left axillary lymphadenopathy. (B) ¹⁸F-fluoroestradiol positron emission tomography with multiple estrogen receptor-positive right suspicious bilateral supraclavicular (red arrow), subpectoral, and axillary nodes with residual ¹⁸F-fluoroestradiol tracer in the draining vein from the injection site.

Additionally, computed tomography of the chest, abdomen, and pelvis and bone scan were negative for distant metastatic disease. Based on mammogram, ultrasound, computed tomography, and bone scan, the patient was clinically staged as stage IIB (cT2, cN1, cM0, grade 2, ER+, PR+, and HER2-negative). Genetic testing was negative for germline pathogenic variants across all analyzed genes. Bilateral axillary adenopathy was noted on clinical examination. An extensive laboratory assessment and pathologic review of biopsied nodes showed no clear etiology for her widespread adenopathy.

She underwent neoadjuvant chemotherapy (NAC) with 4 cycles of docetaxel and cyclophosphamide. Because the patient had persistent bilateral indeterminate nodes in the axilla, infraclavicular, and SCV fossae after completing NAC, an FES-PET was recommended to clarify pathologic nodal involvement. If the lymphadenopathy had decreased or resolved following NAC, it would have raised clinical suspicion for malignant involvement. However, because the nodes persisted, additional diagnostic evaluation was recommended by radiology, because they remained suspicious despite a prior negative biopsy. FES-PET revealed uptake within the soft tissue density in the right breast along the biopsy clip. Scattered throughout the right SCV, subpectoral, and axillary nodal basins, several nodes showed intense FES-PET uptake, suggesting metastatic disease. Interestingly, several adjacent moderately enlarged nodes in these nodal basins did not show increased uptake, suggesting selective tumor nodal involvement despite widespread benign adenopathy. Furthermore, there was no uptake in contralateral axillary or SCV nodes that were enlarged on ultrasound imaging. Despite the prior negative ipsilateral SCV FNA, increased uptake in several SCV nodes on the PET scan led to restaging of cT2N3 disease for radiation planning purposes, overall stage IIIC versus previous IIB.

Ultimately, the patient enrolled in the prospective Trial Of PreoperAtive radiation (TOPAz) randomized controlled trial (NCT05774678), investigating hypofractionated RT with conventional fractionated RT prior to mastectomy and autologous reconstruction, and was randomized to the hypofractionated RT arm.⁷ She received 4005 cGy in 15 fractions to the right breast and regional nodes, followed by a sequential 1200 cGy boost in 6 fractions to the right high-level II, level III, and SCV nodes, with simultaneous integrated boost delivering a total of 1500 cGy in 6 fractions to the grossly involved nodes, because these were not anticipated to be removed at the time of surgery. After completion of RT, she then underwent a right skin-sparing mastectomy and axillary lymph node dissection, with pathologic review revealing a 7.0 × 5.0 cm tumor bed with 10 cm of ductal carcinoma in situ, extensive lymphovascular invasion, and 10 of 13 lymph nodes positive for malignancy, with the largest nodal focus measuring 7.5 mm and showing extranodal extension, ypT3N3a. She had immediate autologous reconstruction with a free flap.

After surgery, the patient was started on adjuvant ribociclib. At her 6-month follow-up, she was doing well, with no radiographic evidence of disease persistence or recurrence and resolution of bilateral lymphadenopathy.

Discussion

Although FES-PET has many clinical applications, it is not routinely used to assist with locoregional staging or RT target delineation. The primary goal of RT is to complement surgical resection by eradicating microscopic disease in areas of resection and maximizing tumor control at undissected involved sites, while simultaneously minimizing toxicity to nearby critical structures; therefore, accurate delineation of active disease is imperative.⁸ Coregistration of diagnostic imaging, including magnetic resonance imaging and FDG-PET, in the treatment planning system is commonly used to more precisely define radiation targets.⁹ In this case, the high specificity of FES-PET was preferred to confirm the presence of ER+ disease in the SCV fossa. FES-PET successfully identified ER+ disease in scattered nodes in the SCV fossa among diffusely enlarged benign nodes, making it a superior diagnostic tool to biopsy in her case. Additionally, FDG-PET can also show increased uptake in benign etiologies of lymphadenopathy, including sarcoidosis, leading to diagnostic ambiguity.¹⁰ The FES-PET findings were critical in determining both active ER+ disease and at-risk nodal basins. Specifically, pathologic involvement of the ipsilateral SCV nodes on FES-PET, which were adjacent to biopsy-negative enlarged nodes on ultrasound, resulted in both extension of the radiation field and increased radiation dose. The superior border of the SCV field was moved from the bottom of the cricoid to the bottom of the mandible (Fig. 2A). Additionally, given the pathologic involvement seen on FES-PET, a boost to the involved nodal region was recommended. Without FES-PET and based on the negative biopsy of an ipsilateral SCV node, the superior border of that field would have been set at the level of the cricoid, and no sequential boost to this region would have been recommended¹¹ (Fig. 2B). It is unclear whether the initial negative SCV biopsy was because of an involved node adjacent to biopsied benign adenopathy or to a false-negative biopsy, because the false-negative rate of FNA has been reported as approximately 30%.¹² Further research is needed to determine the added benefit of FES-PET over ultrasound and FNA alone in the diagnostic staging process of ER-expressing tumors, because in the absence of FES-PET, the at-risk nodal basins in the ipsilateral neck would have been inadequately covered for this patient and underdosed, leading to a higher risk of locoregional failure. Although FES-PET is not routinely recommended, it may be helpful for patients with ER+ disease to discern pathologic nodal involvement and guide subsequent treatment recommendations, especially in challenging cases with indeterminate diagnostic workup and strong clinical concern for pathologic nodal involvement with discordant biopsy results.

Figure 2.

Radiation treatment fields and doses. (A) Coronal view of comprehensive breast treatment plan, including the whole breast volume (red), axillary nodal volume (blue), internal mammary nodal volume (green), and suspicious bilateral supraclavicular (SCV) nodal volume (purple) to the level of the mandible with pathologically involved SCV nodes. (B) The red line delineates the superior border of the SCV field at the level of the cricoid in an SCV node-negative neck. Given pathologic involvement on ¹⁸F-fluoroestradiol positron emission tomography, the high-level II, level III, and SCV nodes were boosted to (C) 1200 Gy in 6 fractions (green), and the gross positive nodes were boosted to (D) 1500 cGy in 6 fractions (blue).

When using FES to help delineate active disease, it is important to note that residual FES may be detected in the draining vein from the injection site¹³ (Fig. 1C). Additionally, identifying metastatic liver disease is limited by the liver’s high physiological uptake.² In this case, the patient’s extensive contralateral adenopathy is undergoing further workup, with the differential remaining broad, including infectious etiologies, autoimmune conditions, and indolent malignancy.

Conclusions

In clinical situations where the extent of disease may be unclear, FES-PET can help delineate RT targets and inform RT dose.

Disclosures

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.