Research ArticleClinical Investigation

68Ga-FAPI PET/CT as an Alternative to 18F-FDG PET/CT in the Imaging of Invasive Lobular Breast Carcinoma

Ertan Sahin, Tulay Kus, Alper Aytekin, Evren Uzun, Umut Elboga, Latif Yilmaz, Yusuf B. Cayirli, Merve Okuyan, Vuslat Cimen and Ufuk Cimen
Journal of Nuclear Medicine March 2024, jnumed.123.266798; DOI: https://doi.org/10.2967/jnumed.123.266798

Abstract

Accurate staging of invasive lobular carcinoma (ILC), a subtype of breast cancer, is vital for effective clinical management. Although 18F-FDG PET/CT is a commonly used tool, its efficacy varies across different histologic subtypes. To mitigate this challenge, our investigation delves into the potential utility of 68Ga-fibroblast activation protein inhibitor (FAPI) PET/CT as an alternative for staging ILC, aiming to address a significant research gap using a more expansive patient cohort than the smaller samples commonly found in the existing literature. Methods: In this retrospective analysis, women diagnosed with primary ILC of the breast underwent both 18F-FDG PET/CT and 68Ga-FAPI PET/CT. Both modalities were compared across all lesion locations with the used reference standard. The interval between scans was 1 wk, without any intervening treatments. Lesions were categorized visually, and tracer activity was analyzed using SUVmax, tumor-to-background uptake ratio, and uptake ratios. Both modalities were compared across various parameters, and statistical analysis was performed using SPSS 22.0. A P value of less than 0.05 was chosen to determine statistical significance. Results: The study included 23 female ILC patients (mean age, 51 y) with hormone-positive, human epidermal growth factor receptor type 2–negative tumors. Most (65%) had the luminal A subtype. 68Ga-FAPI PET/CT outperformed 18F-FDG PET/CT, with higher tumoral activity and tumor-to-background uptake ratios (P < 0.001). Primary tumors showed significantly increased uptake with 68Ga-FAPI PET/CT (P < 0.001), detecting additional foci, including multicentric cancer. Axillary lymph node metastases were more frequent and had higher uptake values with 68Ga-FAPI PET/CT (P = 0.012). Moreover, 68Ga-FAPI PET/CT identified more lesions, including bone and liver metastases. Pathologic features did not significantly correlate with imaging modalities, but a positive correlation was observed between peritumoral lymphocyte ratio and 68Ga-FAPI PET/CT–to–18F-FDG PET/CT uptake ratios (P = 0.026). Conclusion: This study underscores 68Ga-FAPI PET/CT’s superiority over 18F-FDG PET/CT for ILC. 68Ga-FAPI PET/CT excels in detecting primary breast masses, axillary lymph nodes, and distant metastases; can complement 18F-FDG PET/CT in ILC; and holds potential as an alternative imaging method in future studies.

Breast cancer is the most common cancer in women worldwide, comprising 25% of female cancer cases (1). Invasive lobular carcinoma (ILC) accounts for about 10% of all invasive breast cancer cases (2,3). Precise clinical staging is crucial for treatment decisions and prognosis (4,5).

Staging methods combine systemic and local assessments. Systemic staging uses various diagnostic tools such as bone scans, abdominal CT/MRI, thoracic CT, and 18F-FDG PET. Local disease extent is determined with mammography, ultrasound, and breast MRI (6). 18F-FDG PET/CT, crucial for breast cancer management, aids in initial staging, restaging, treatment response evaluation, and recurrence detection (7).

The utility of 18F-FDG PET/CT, however, exhibits variability among histologic subtypes, particularly in the case of ductal and lobular breast cancers. The inherent challenges of identifying ILC with 18F-FDG PET/CT stem from distinct molecular and pathologic features, including lower cellular density, receptor expression, and metastatic patterns (2,3); furthermore, primary and metastatic ILC is less 18F-FDG–avid than invasive ductal cancer (IDC), leading to the weakness of 18F-FDG PET for ILC (8,9). Additionally, factors such as small tumor size (<1 cm), in situ carcinomas, micrometastases, low-grade tumors, and benign pathologies can compromise the sensitivity and specificity of 18F-FDG PET/CT in breast cancer (10–12).

To address limitations, prior research explored alternatives such as 18F-fluoroestradiol, especially for ILC (13,14). Recently, a new radiopharmaceutical targeting fibroblast activation protein (FAP) has gained attention for tumor diagnosis and staging. FAP, highly expressed in cancer-associated fibroblasts (CAFs) (15–18), shows promise in PET studies, especially in combination with 68Ga, due to favorable pharmacokinetics and high tumor background activity (19–22).

The unique role of the tumor stroma and the abundant stromal expression of FAP in primary breast cancer suggest a potential for high accuracy in FAPI-directed imaging (23,24). Recent studies have emerged comparing 18F-FDG PET/CT and 68Ga-FAPI PET/CT in breast cancer (25–27). Recent studies, including one by Eshet et al., compare 18F-FDG PET/CT and 68Ga-FAPI PET/CT in breast cancer, specifically in patients with ILC, albeit within a limited cohort (25–27).

Motivated by the paucity of literature on this subject, this study aimed to evaluate whether 68Ga-FAPI PET/CT outperforms 18F-FDG PET/CT in the context of ILC, with a focus on a larger patient cohort.

MATERIALS AND METHODS

Patient Selection and Evaluation

This study, approved by the Institutional Clinical Research Ethics Committee, included 23 women with ILC. They underwent 18F-FDG PET/CT and 68Ga-FAPI PET/CT for staging before systemic chemotherapy or surgery (Fig. 1). Secondary confirmation methods, such as bone scintigraphy–radiologic imaging or repeat 68Ga-FAPI PET/CT, were routinely used because of potential limitations in 18F-FDG PET/CT for the ILC subtype. The interval between scans was limited to 1 wk, with no intervening treatments. Eligible patients were 18 y old or older, with no recent systemic treatment or radiotherapy and a confirmed diagnosis of ILC. All provided written informed consent. Exclusions comprised men, individuals under 18 y old, secondary malignancy, severe hepatic–renal impairment, pregnancy, and breastfeeding.

FIGURE 1.
FIGURE 1.

Descriptive flowchart of study.

Patient Preparation and PET/CT Imaging Protocols

18F-FDG PET/CT

The patients underwent a standardized preparation regimen before the 18F-FDG PET/CT imaging session, including a 12-h fast. Blood glucose levels had to be below 150 mg/dL. A 5 MBq/kg dose of 18F-FDG was administered intravenously. Sixty minutes later, imaging was conducted using a Discovery IQ PET/CT device (GE Healthcare), scanning from the vertex to the mid femur.

68Ga-FAPI PET/CT

68Ga-FAPI was synthesized and labeled using the Modular Lab-Easy system (Eckert & Ziegler) in a modular laboratory at our center, following a procedure akin to prior studies (18,19). Quality control assessments using thin-layer chromatography and high-performance liquid chromatography affirmed a radiochemical purity exceeding 98%. Subsequently, a 2–3 MBq/kg dose of synthesized 68Ga-FAPI was intravenously injected into patients. Forty-five minutes later, PET/CT imaging was conducted using the Discovery IQ PET/CT device, covering the vertex to the mid femur.

Pathologic Evaluation

In the pathologic assessment, specimens obtained through Tru-Cut (Merit Medical) biopsy and excision were confirmed as malignant on the basis of criteria such as anaplasia, absence of myoepithelial cells, and the presence of mitosis or necrosis. Cases were evaluated for histologic tumor type, presence of ductal or lobular carcinoma in situ, nuclear grade, tumor-to-stroma ratio, and lymphocyte density and were graded using the Nottingham histologic scoring system.

Immunohistochemistry on tissue sections assessed estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2/neu expression. Estrogen receptor and progesterone receptor were evaluated in decimal percentiles, with staining intensity graded as weak, moderate, or strong. Invasive carcinomas with estrogen receptor and progesterone receptor between 1% and 10% were considered low positive, less than 10% staining was negative (score 1), and intense staining in more than 10% was positive (score 3). Human epidermal growth factor receptor 2/neu–equivocal cases were verified with human epidermal growth factor receptor 2 silver in situ hybridization, categorizing tumors into 5 molecular subtypes based on immunohistochemical results.

Evaluation of Images and Patient-Lesion Analysis

Two experienced nuclear medicine physicians meticulously reviewed the PET/CT images, categorizing lesions as positive if detected by at least 1 specialist and negative if not detected. Classification of lesions without histopathologic confirmation was based on imaging methods (ultrasound, mammography, CT, MRI) and clinical findings. Histopathologic examination was conducted for 5 axillary lymph nodes in metastatic lesions, whereas decisions for other sites relied on imaging methods and clinical data.

For both PET/CT methods, areas with higher uptake than background were assessed as positive; findings from other modalities were also considered in the assessment. Images in axial, coronal, and sagittal planes were available for review. Semiquantitative analysis used SUVmax, with volumes of interest around primary breast lesions in 3 planes for both scans. SUVmax for primary lesions and metastases was determined, and radiopharmaceutical uptake exceeding background was quantified using SUVmax and tumor-to-background uptake ratio. The obtained imaging findings from both PET/CT methods were compared on both a patient basis and a lesion basis for further analysis and interpretation. Staging was done according to the method of the American Joint Committee on Cancer (28).

Reference Standard

All patients who were evaluated had been discussed in the multidisciplinary council for breast cancer before the data were scanned retrospectively. This council includes departments such as medical oncology, radiation oncology, general surgery, medical pathology, radiology, and nuclear medicine. Additional foci observed in PET/CT imaging for multifocal or multicentric primary malignancies, which had not undergone histopathologic testing, were further assessed using previous mammography and MRI results to determine malignancy. If there was no histopathologic evidence, regional lymph nodes observed in PET/CT imaging were correlated with previous ultrasonographic and MRI results, taking into account their molecular and morphologic characteristics depicted in the PET/CT imaging.

Moreover, the molecular and morphologic properties of distant lymph node, visceral, and bone involvement reported through PET/CT imaging were evaluated alongside routinely performed conventional imaging, as for breast lesions and regional lymph nodes. Finally, alignment of the latest decisions with the conclusions documented by the multidisciplinary council was ensured through consensus, also considering treatment response evaluations across all lesion sites during follow-up periods. The median follow-up was 4 mo (range, 3–6 mo). Consequently, the integration of multiple diagnostic modalities and multidisciplinary discussions formed a robustly constructed reference standard.

Statistical Analysis

The study data underwent descriptive statistical analysis, presenting numeric variables as mean and SD and categoric variables through frequency and percentage analysis. The normality and homogeneity of variance were tested using the Shapiro–Wilk and Levene tests, respectively. For nonnormally distributed dependent variables, the Wilcoxon signed-rank test was used, whereas the Mann–Whitney U test compared nonnormally distributed independent variables. Continuous variables were evaluated with the Pearson correlation test, and categoric variables with the Spearman correlation test. SPSS 22.0 software was used for statistical analyses, with the significance level set at a P value of less than 0.05.

RESULTS

Patient Demographics and Tumor Characteristics

In total, 23 women with ILC were enrolled in this study. Their mean age was 51 y (range, 37–79 y), with 8 being premenopausal. Before undergoing PET/CT, 4 patients had undergone breast surgery. Additionally, 2 patients had bilateral breast cancer involvement (Fig. 2). The pathologic and clinical characteristics of the patients are summarized in Table 1.

FIGURE 2.
FIGURE 2.

Maximum-intensity projection 18F-FDG PET (left) and 68Ga-FAPI PET (right) images of synchronous ILC. (A) 42-y-old patient with multicentric primary lesions (encircled), regional (solid arrows), and distant inferior jugular lymph node (dashed arrows) seen on 18F-FDG PET and subsequently confirmed on 68Ga-FAPI PET, which also revealed additional malignant foci aligned with MRI. Some lesions exhibited high activity retention on 68Ga-FAPI PET. (B) 53-y-old patient showing no significant uptake on 18F-FDG PET but synchronous bilateral lesions (arrows) on 68Ga-FAPI PET, which also identified pathologic lymph nodes (encircled), resulting in upstaging. SUVbw = body-weight SUV.

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TABLE 1.

Clinical and Pathologic Features of Patients

Comparative PET/CT Analysis

The study revealed that 68Ga-FAPI PET/CT exhibited increased tumoral activity retention, along with elevated tumor-to-background uptake ratios, in comparison to 18F-FDG PET/CT, across all lesion locations (13.22 ± 8.1 vs 3.43 ± 2.12; P < 0.001; z = −3.621). Furthermore, significantly increased 68Ga-FAPI uptake (mean, 13.8 ± 5.1) was detected in primary tumoral lesions compared with 18F-FDG uptake (mean, 3.9 ± 3.0; P < 0.001; z = 3.621) (Table 2; Figs. 3 and 4).

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TABLE 2.

SUVmax of 18F-FDG PET/CT and 68Ga-FAPI PET/CT According to Lesion Location

FIGURE 3.
FIGURE 3.

Maximum-intensity projection 18F-FDG PET (left) and 68Ga-FAPI PET (right) images (A) and axial hybrid 18F-FDG PET/CT (left) and 68Ga-FAPI PET/CT (right) images (B–D) of 50-y-old patient with right bifocal ILC. (A and B) Two adjacent breast lesions with low 18F-FDG PET/CT uptake showed significantly higher uptake on 68Ga-FAPI PET/CT (solid arrows). Dashed arrows in right panel indicate regional lymph nodes detected by FAPI PET/CT. (C and D) Axillary lymph nodes (arrows) without activity on 18F-FDG PET/CT exhibited significant uptake on 68Ga-FAPI PET/CT, leading to upstaging in N category. SUVbw = body-weight SUV.

FIGURE 4.
FIGURE 4.

Maximum-intensity projection 18F-FDG PET (left) and 68Ga-FAPI PET (right) images (A), axial hybrid 18F-FDG PET/CT (left) and 68Ga-FAPI PET/CT (right) images (B and C), and axial CT images (D) of 42-y-old patient with right ILC. (A and B) Although 18F-FDG PET/CT showed no significant activity in right breast lesion (white arrows), 68Ga-FAPI PET/CT revealed substantial uptake. Dashed arrow in right panel A indicates liver lesion, whereas solid arrow indicates primary lesion. (C and D) In addition, liver lesion with vague borders on CT images (arrows) had no significant 18F-FDG uptake but exhibited high 68Ga-FAPI uptake, confirmed as breast cancer metastasis through MRI, indicating stage IV disease. SUVbw = body-weight SUV.

Among the 23 patients, 19 had a primary breast lesion, whereas 4 had previously undergone mastectomy. Among those with a primary breast lesion, 6 had a solitary breast lesion, and 13 had multicentric breast cancer. The median size of primary breast lesions was 20.5 mm (range, 3–80 mm). In total, 44 breast lesions were analyzed, with only 2 lesions in the breast measuring less than 8 mm, indicating that all lesions were likely to be 18F-FDG PET/CT–avid. Although the number of primary breast lesions detected was identical for both 18F-FDG PET/CT and 68Ga-FAPI PET/CT (25 lesions), 68Ga-FAPI PET/CT identified an additional 19 foci (Table 3). Notably, among the 7 patients initially assessed as having solitary breast cancer based on 18F-FDG PET/CT, 68Ga-FAPI PET/CT revealed them to have multicentric breast cancer. Moreover, 68Ga-FAPI PET/CT detected a higher number of multicentric foci in 3 patients. Additionally, 4 patients exhibited nonavid lesions in the contralateral breast on 18F-FDG PET/CT that were detectable on 68Ga-FAPI PET/CT. No correlation was observed between the size of primary breast lesions and either 18F-FDG PET/CT uptake (P = 0.33; r = 0.151) or 68Ga-FAPI PET/CT uptake (P = 0.19; r = 0.201), possibly because most lesions were 1 cm or larger, where 18F-FDG sensitivity is already higher.

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TABLE 3.

Comparison of Lesion Number on 18F-FDG PET/CT and 68Ga-FAPI PET/CT According to Location

Axillary lymph node metastasis was detected in 1 patient with 18F-FDG PET/CT and in 8 patients with 68Ga-FAPI PET/CT. The mean uptake value of 68Ga-FAPI PET/CT (11.5 ± 5.9) was significantly higher than that of 18F-FDG PET/CT (1.15 ± 0.8; P = 0.012; z = 2.521) (Table 2; Figs. 2 and 3). In total, 134 lymph nodes were measured, with short diameters ranging from 5 to 18 mm. Among them, 89.5% had a short diameter of 8 mm or less. Both 18F-FDG PET/CT and 68Ga-FAPI PET/CT showed involvement in 6 lymph nodes (4.5%). 18F-FDG PET/CT demonstrated no uptake in 34 lymph nodes, whereas 68Ga-FAPI PET/CT exhibited uptake in 25.4% of these nodes. Ninety-four lymph nodes were classified as benign by both imaging modalities (70.1%). Of the 40 metastatic lymph nodes, 30 were at level 1, and the rest were at level 2. There was a strong positive correlation between lymph node short diameter and 18F-FDG PET/CT uptake values (P < 0.001; r = 0.625), whereas higher accumulation on 68Ga-FAPI PET/CT resulted in higher sensitivity, and these lesions suffered less from the partial-volume effect (P < 0.001; r = 0.319).

Regarding metastatic sites, in 18 of 23 (78.2%) patients 68Ga-FAPI PET/CT identified new lesions not seen on 18F-FDG PET/CT, including multifocal primary lesions within the breast, local or distant lymph nodes, bone, and liver (Table 3; Figs. 4 and 5). Although 1 distant lymph node metastasis was detected on 18F-FDG PET/CT, 68Ga-FAPI PET/CT revealed an additional 3 patients with distant lymph node metastasis (mean, 3.0 and 8.5 ± 2.8, respectively). Bone metastases were detected in 7 of 8 patients on 18F-FDG PET/CT, and an additional patient with bone metastasis was identified using 68Ga-FAPI PET/CT. The total number of bone metastases detected on 18F-FDG PET/CT was 264, compared with 473 on 68Ga-FAPI PET/CT (Table 3; Fig. 5). In 87.5% of patients, the number of bone metastases detected by 68Ga-FAPI PET/CT was higher than that detected by 18F-FDG PET/CT. The mean uptake of 68Ga-FAPI PET/CT was 19.1 ± 6.0, whereas it was 5.3 ± 4.1 for 18F-FDG PET/CT (P = 0.017; z = 2.380) (Table 2). Furthermore, 3 new solitary liver metastases, undetectable on 18F-FDG PET/CT, were visualized using 68Ga-FAPI PET/CT (mean, 6.37 ± 3.5) (Table 3; Fig. 4).

FIGURE 5.
FIGURE 5.

Maximum-intensity projection 18F-FDG PET (left) and 68Ga-FAPI PET (right) images (A) and axial hybrid 18F-FDG PET/CT (left) and 68Ga-FAPI PET/CT (right) images (B and C) of 68-y-old patient with left ILC. (A and B) Notable difference in uptake between 18F-FDG PET/CT and 68Ga-FAPI PET/CT was observed in left breast lesion (solid arrow). Multiple disseminated focal uptakes (dashed arrows) corresponding to predominantly 68Ga-FAPI–avid bone lesions were detected, including in calvarium and vertebral column. (B and C) Most bone lesions (arrows) showed osteolytic features in both 18F-FDG PET/CT and 68Ga-FAPI PET/CT, with high 68Ga-FAPI avidity. SUVbw = body-weight SUV.

The TNM classification and staging of 23 patients were compared between 2 imaging modalities. T categories were assessed in 19 patients, with operated cases classified as Tx. Both modalities showed a similar distribution among T category groups (Tx, T1, T2, T3, and T4). N category variations were observed: 18F-FDG PET/CT showed 88% N0, 8% N1, and 4% N3, whereas 68Ga-FAPI PET/CT showed 52%, 44%, and 4%, respectively, with 36% upstaging in N0 cases. Both modalities had comparable results for the M category, but 68Ga-FAPI PET/CT revealed a 13% upstaging rate, indicating its ability to detect additional metastatic lesions. Lastly, the anatomic stage group analysis revealed 1 case (4.4%) as stage IA, 11 cases (47.8%) as IIA, 1 case (4.4%) as IIB, 1 case (4.4%) as IIIB, and 9 cases (39.1%) as IV. The single case identified as IA on 18F-FDG PET/CT was later identified as IIA on 68Ga-FAPI PET/CT, also in line with the reference standard. Similarly, 3 of the cases identified as IIA, 1 case identified as IIB, and 2 cases identified as IIA were later upstaged by 68Ga-FAPI PET/CT to IIB, IV, and IV, respectively (Table 4).

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TABLE 4.

Comparison of TNM Classifications and Anatomic Stage Groups Between 2 Modalities

Correlation Analysis of Imaging Uptake Ratios and Pathologic Features

The mean uptake value in patients with luminal A disease was 4.42 ± 3.66 by 18F-FDG PET/CT, whereas it was 2.44 ± 0.23 in the luminal B subgroup (P = 0.092). Correspondingly, these values were 13.6 ± 5.4 and 14.6 ± 5.7 by 68Ga-FAPI PET/CT (P = 0.706). There was no correlation between the luminal A or B subgroup and the ratio of 18F-FDG PET/CT to 68Ga-FAPI PET/CT SUVmax (P = 0.102; r = −0.42).

Moreover, no significant correlation was found between the other pathologic features of tumor and the uptake ratio of 18F-FDG to 68Ga-FAPI PET/CT (glandular differentiation [r = 0.32; P = 0.17], nuclear polymorphism [r = 0.23; P = 0.34], mitosis count [r = 0.31; P = 0.18], grade score [r = 0.38; P = 0.099], grade [r = 0.19; P = 0.43], or tumor-to-stroma ratio [r = 0.29; P = 0.21]). In contrast, a moderately significant positive correlation was observed between the peritumoral lymphocyte ratio and the 68Ga-FAPI PET/CT–to–18F-FDG PET/CT SUVmax ratio (r = 0.498; P = 0.026). This suggests that a higher peritumoral lymphocyte ratio was associated with a higher uptake ratio of 68Ga-FAPI PET/CT to 18F-FDG PET/CT.

DISCUSSION

False-negative rates are higher for ILCs than for ductal breast cancers. Although MRI demonstrates high sensitivity in detecting primary breast masses and axillary lymph nodes, 18F-FDG PET serves as the most valuable tool for identifying distant metastases. In the presence of ILC, a secondary imaging method becomes necessary. Given that the stroma volume can surpass that of neoplastic cells, 68Ga FAPI PET/CT appears to offer greater sensitivity than 18F-FDG PET/CT, especially for detecting small lesions or those with low or heterogeneous glucose metabolism.

The limited sensitivity of 18F-FDG PET/CT may be attributed not only to the low-grade nature of ILC but also to its pathogenetic characteristics. E-cadherin, a calcium-dependent transmembrane protein responsible for maintaining tissue integrity and cell-to-cell adhesion while preventing tissue invasion (29), is absent in approximately 85% of cases of ILC. This absence leads to a loss of adhesion proteins and disrupts the morphologic pattern, resulting in tumor cells that are individually dispersed or arranged in a single-file pattern, loosely distributed throughout a fibrous matrix with minimal desmoplastic response (30). Additionally, the tumor-infiltrating lymphocyte rate is typically low. Theoretically, the unique nature of ILC may reduce the sensitivity of 18F-FDG PET/CT because of the dispersion of glucose-intensive tumor tissue; however, this may not affect the effectiveness of 68Ga-FAPI PET/CT.

Although the benefits of 68Ga-FAPI PET/CT have been demonstrated in numerous studies involving small patient cohorts (31), it is not yet routinely recommended by national guidelines because of the lack of high-level evidence. Initially, Kömek et al. conducted a prospective study on 20 patients with breast cancer, demonstrating that the sensitivity and specificity of 68Ga-FAPI PET/CT in detecting primary breast lesions were 100% and 95.6%, respectively. In comparison, the sensitivity and specificity of 18F-FDG PET/CT were 78.2% and 100%, respectively (25). Subsequently, Elboga et al. conducted a retrospective study on 48 invasive breast cancer patients, revealing that 68Ga-FAPI PET/CT detected a higher number of primary breast lesions and new metastatic lesions with higher uptake values than did 18F-FDG PET/CT (26). The effectiveness of 18F-FDG PET/CT was decreasing, especially in the ILC subtype, highlighting the need for a more effective imaging method, particularly in this patient group. In a prospective study by Alçın et al., which included 11 cases of ILC (32), patients with low avidity as determined by 18F-FDG PET/CT scans were examined. The study found that 68Ga-FAPI PET/CT yielded higher sensitivity and higher SUVmax than did 18F-FDG PET/CT in breast cancer patients with low 18F-FDG affinity. Additionally, 68Ga-FAPI PET/CT identified additional lesions in the primary region, lymph nodes, and 1 lung metastatic nodule. Another prospective pilot trial involving 7 ILC patients with disease that was not 18F-FDG–avid indicated that 68Ga-FAPI PET/CT detected an increased number of lesions compared with CT alone (P = 0.022) (27).

Examining these studies reveals a lack of specificity and limited patient numbers within the ILC subgroup. Therefore, our retrospective study comparing 68Ga-FAPI PET/CT with 18F-FDG PET/CT in ILC patients holds significance for data accumulation and knowledge expansion. With a larger patient cohort than other studies, our findings show that 68Ga-FAPI PET/CT detected more lesions and exhibited high tumor-to-background uptake ratios. Regardless of pathologic features, new lesions in the primary breast, local or distant lymph nodes, bone, and liver were found in 73.9% of patients using 68Ga-FAPI PET/CT compared with 18F-FDG PET/CT.

We studied 44 breast lesions, with only 2 having a size less than 8 mm. Although all lesions likely showed 18F-FDG PET/CT uptake regardless of size, 68Ga-FAPI PET/CT identified 19 additional foci. MRI is more specific for primary breast lesions; however, 68Ga-FAPI PET/CT, though not a replacement, has demonstrated superiority over 18F-FDG PET/CT in previous studies.

Both 18F-FDG PET/CT and 68Ga-FAPI PET/CT consistently assessed tumor sizes in various T categories, showing agreement in primary tumor evaluation. Despite differences in N category analysis, 68Ga-FAPI PET/CT exhibited higher sensitivity, leading to a 36% upstaging from N0 cases initially identified by 18F-FDG PET/CT. Although overall M category results were comparable, 68Ga-FAPI PET/CT revealed a 13% upstaging rate, detecting additional metastatic lesions. This has significant implications for treatment planning and prognosis assessment. Anatomic stage group analysis highlighted nuanced diagnostic capabilities, especially reclassifying regional diseases from stage III to IV in 68Ga-FAPI PET/CT compared with 18F-FDG PET/CT.

In our study a moderately significant positive correlation was identified between the peritumoral lymphocyte ratio and the ratio of 68Ga-FAPI PET/CT to 18F-FDG PET/CT (r = 0.498; P = 0.026). In a translational study conducted by Costa et al. (33), distinct subsets of CAFs within breast cancer were identified and labeled as CAF-S1 through CAF-S4, and CAF-S1 fibroblasts were associated with the infiltration of FOXP3+ T lymphocytes in breast cancer cases. In line with these findings, the observed correlation between peritumoral lymphocyte infiltration and FAPI involvement suggests that this connection could potentially serve as an indicative measure of FAP’s function within immune modulation.

In addition to its success in detecting primary lesions, 68Ga-FAPI PET/CT also excelled in detecting lymph node uptake. Our study showed that 68Ga-FAPI PET/CT identifies axillary lymph node metastases more effectively than 18F-FDG PET/CT does. Despite morphologic suspicions in 18F-FDG PET/CT, 89.5% of nodes with a short diameter of 8 mm or less did not exhibit 18F-FDG uptake. Unlike 18F-FDG, 68Ga-FAPI uptake displayed a weak correlation with lymph node size, suggesting size-independent uptake.

Consistent with the studies mentioned previously, 68Ga-FAPI PET/CT appeared to be superior to 18F-FDG PET/CT in detecting distant metastases in our study (25–27,32).

Eshet et al. conducted a prospective pilot trial that indicated that 68Ga-FAPI PET/CT detected more lesions than CT alone (P = 0.022) in 7 ILC patients whose disease was not 18F-FDG–avid (27). A notable aspect of this study is that metastatic or progressing sites were poorly demonstrated not only by 18F-FDG PET/CT but also by conventional CT and bone scans. This suggests that secondary imaging methods may be inadequate for recognizing the ILC subtype. Furthermore, in this case series, 68Ga-FAPI PET/CT revealed more extensive skeletal disease, aligning with our findings.

In the present study, the number of bone metastases was increased on 68Ga-FAPI PET/CT compared with 18F-FDG PET/CT in 7 of 8 patients (87.5%). The mean 68Ga-FAPI uptake for bone metastasis was significantly higher than the mean 18F-FDG uptake (P = 0.017; z = 2.380).

We found 3 liver metastases missed by 18F-FDG PET/CT but detectable with 68Ga-FAPI PET/CT. Building on our previous research (26), we argue that 68Ga-FAPI PET/CT, with its low liver background activity, enhances liver metastasis detection, evident in the high tumor-to-background uptake ratios.

Despite 68Ga-FAPI PET/CT’s capability to reveal new breast lesions, their significance should be confirmed histopathologically or considered primary on the basis of MRI results. The primary value of 68Ga-FAPI PET/CT lies in detecting regional lymph node and distant metastases, especially when other imaging modalities such as ultrasound, CT, and bone scintigraphy may be insufficient for primary breast lesions.

There are limited studies, as mentioned earlier, comparing 68Ga-FAPI PET/CT and 18F-FDG PET/CT head to head, and these studies include only a low number of ILC patients (27,32). Our study, with the highest number of ILC cases to our knowledge, offers a comprehensive comparison between 18F-FDG and 68Ga-FAPI PET/CT, making a unique contribution to the literature. It highlights the ability of 68Ga-FAPI PET/CT to lower false-negative rates compared with 18F-FDG PET/CT.

Although our case number was relatively high compared with the limited studies on this subject in the literature, our main limitation is the relatively low case count. Other important limitations include the lack of a prospective randomized study design and the absence of histopathologic confirmation for all metastatic lesions, excluding primary breast lesions and target lesions.

CONCLUSION

Our study contributes to the evidence supporting 68Ga-FAPI PET/CT’s utility in ILC, including staging. Nuanced differences, especially in lymph node involvement and metastatic lesion detection, underscore its complementary role with 18F-FDG PET/CT. These insights can inform clinical decisions, providing a more comprehensive understanding of disease extent and refining treatment strategies for breast cancer patients. Larger-cohort studies are needed to validate and build on these initial findings.

DISCLOSURE

No potential conflict of interest relevant to this article was reported.

KEY POINTS

QUESTION: Is 68Ga-FAPI PET/CT a more useful imaging method than 18F-FDG PET/CT in ILC?

PERTINENT FINDINGS: In this cohort study examining 23 women with ILC, 68Ga-FAPI PET/CT appeared to be superior to 18F-FDG PET/CT in showing the primary lesion and metastases of the lymph nodes and other organs.

IMPLICATIONS FOR PATIENT CARE: 68Ga-FAPI PET/CT might become a viable alternative to 18F-FDG PET/CT based on the outcomes of future studies involving larger patient cohorts.

Footnotes

  • Published online Mar. 14, 2024.

REFERENCES

  1. 1.↵
    1. Ferlay J,
    2. Soerjomataram I,
    3. Dikshit R,
    4. et al
    . Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–E386.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Li CI,
    2. Anderson BO,
    3. Daling JR,
    4. et al
    . Trends in incidence rates of invasive lobular and ductal breast carcinoma. JAMA. 2003;289:1421–1424.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Li CI,
    2. Daling JR
    . Changes in breast cancer incidence rates in the United States by histologic subtype and race/ethnicity, 1995 to 2004. Cancer Epidemiol Biomarkers Prev. 2007;16:2773–2780.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    1. Siegel RL,
    2. Miller KD,
    3. Jemal A
    . Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Goetz MP,
    2. Gradishar WJ,
    3. Anderson BO,
    4. et al
    . NCCN guidelines insights: breast cancer version, 3.2018. J Natl Compr Canc Netw. 2019;17:118–126.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Lebron-Zapata L,
    2. Jochelson MS
    . Overview of breast cancer screening and diagnosis. PET Clin. 2018;13:301–323.
    OpenUrl
  7. 7.↵
    1. Kitajima K,
    2. Miyoshi Y
    . Present and future role of FDG-PET/CT imaging in the management of breast cancer. Jpn J Radiol. 2016;34:167–180.
    OpenUrl
  8. 8.↵
    1. Hogan MP,
    2. Goldman DA,
    3. Dashevsky B,
    4. et al
    . Comparison of 18F-FDG PET/CT for systemic staging of newly diagnosed invasive lobular carcinoma versus invasive ductal carcinoma. J Nucl Med. 2015;56:1674–1680.
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Borst MJ,
    2. Ingold JA
    . Metastatic patterns of invasive lobular versus invasive ductal carcinoma of the breast. Surgery. 1993;114:637–641.
    OpenUrlPubMed
  10. 10.↵
    1. Kumar R,
    2. Chauhan A,
    3. Zhuang H,
    4. et al
    . Clinicopathologic factors associated with false negative FDG-PET in primary breast cancer. Breast Cancer Res Treat. 2006;98:267–274.
    OpenUrlCrossRefPubMed
  11. 11.
    1. Avril N,
    2. Rose CA,
    3. Schelling M,
    4. et al
    . Breast imaging with positron emission tomography and fluorine-18 fluorodeoxyglucose: use and limitations. J Clin Oncol. 2000;18:3495–3502.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. McCart Reed AE,
    2. Kutasovic JR,
    3. Lakhani SR,
    4. Simpson PT
    . Invasive lobular carcinoma of the breast: morphology, biomarkers and ‘omics. Breast Cancer Res. 2015;17:12.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Ulaner GA,
    2. Jhaveri K,
    3. Chandarlapaty S,
    4. et al
    . Head-to-head evaluation of 18F-FES and 18F-FDG PET/CT in metastatic invasive lobular breast cancer. J Nucl Med. 2021;62:326–331.
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    1. Kurland BF,
    2. Peterson LM,
    3. Lee JH,
    4. et al
    . Estrogen receptor binding (18F-FES PET) and glycolytic activity (18F-FDG PET) predict progression-free survival on endocrine therapy in patients with ER+ breast cancer. Clin Cancer Res. 2017;23:407–415.
    OpenUrlAbstract/FREE Full Text
  15. 15.↵
    1. Siveke JT
    . Fibroblast-activating protein: targeting the roots of the tumor microenvironment. J Nucl Med. 2018;59:1412–1414.
    OpenUrl
  16. 16.
    1. Garin-Chesa P,
    2. Old LJ,
    3. Rettig WJ
    . Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci USA. 1990;87:7235–7239.
    OpenUrlAbstract/FREE Full Text
  17. 17.
    1. Hamson EJ,
    2. Keane FM,
    3. Tholen S,
    4. Schilling O,
    5. Gorrell MD
    . Understanding fibroblast activation protein (FAP): substrates, activities, expression and targeting for cancer therapy. Proteomics Clin Appl. 2014;8:454–463.
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Jansen K,
    2. Heirbaut L,
    3. Cheng JD,
    4. et al
    . Selective inhibitors of fibroblast activation protein (FAP) with a (4-quinolinoyl)-glycyl-2-cyanopyrrolidine scaffold. ACS Med Chem Lett. 2013;4:491–496.
    OpenUrl
  19. 19.↵
    1. Loktev A,
    2. Lindner T,
    3. Mier W,
    4. et al
    . A tumor-imaging method targeting cancer associated fibroblasts. J Nucl Med. 2018;59:1423–1429.
    OpenUrlAbstract/FREE Full Text
  20. 20.
    1. Lindner T,
    2. Loktev A,
    3. Altmann A,
    4. et al
    . Development of quinoline-based theranostic ligands for the targeting of fibroblast activation protein. J Nucl Med. 2018;59:1415–1422.
    OpenUrlAbstract/FREE Full Text
  21. 21.
    1. Giesel FL,
    2. Kratochwil C,
    3. Lindner T,
    4. et al
    . 68Ga-FAPI PET/CT: biodistribution and preliminary dosimetry estimate of 2 DOTA-containing FAP-targeting agents in patients with various cancers. J Nucl Med. 2019;60:386–392.
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    1. Kratochwil C,
    2. Flechsig P,
    3. Lindner T,
    4. et al
    . 68Ga-FAPI PET/CT: tracer uptake in 28 different kinds of cancer. J Nucl Med. 2019;60:801–805.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Scanlan MJ,
    2. Raj BK,
    3. Calvo B,
    4. et al
    . Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc Natl Acad Sci USA. 1994;91:5657–5661.
    OpenUrlAbstract/FREE Full Text
  24. 24.↵
    1. Šimková A,
    2. Busek P,
    3. Sedo A,
    4. Konvalinka J
    . Molecular recognition of fibroblast activation protein for diagnostic and therapeutic applications. Biochim Biophys Acta Proteins Proteomics. 2020;1868:140409.
    OpenUrl
  25. 25.↵
    1. Kömek H,
    2. Can C,
    3. Güzel Y,
    4. et al
    . 68Ga-FAPI-04 PET/CT, a new step in breast cancer imaging: a comparative pilot study with the 18F-FDG PET/CT. Ann Nucl Med. 2021;35:744–752.
    OpenUrl
  26. 26.↵
    1. Elboga U,
    2. Sahin E,
    3. Kus T,
    4. et al
    . Superiority of 68Ga-FAPI PET/CT scan in detecting additional lesions compared to 18FDG PET/CT scan in breast cancer. Ann Nucl Med. 2021;35:1321–1331.
    OpenUrl
  27. 27.↵
    1. Eshet Y,
    2. Tau N,
    3. Apter S,
    4. et al
    . The role of 68Ga-FAPI PET/CT in detection of metastatic lobular breast cancer. Clin Nucl Med. 2023;48:228–232.
    OpenUrl
  28. 28.↵
    AJCC Cancer Staging Manual. Springer International Publishing; 2017:589–636.
  29. 29.↵
    1. Vleminckx K,
    2. Vakaet L Jr.,
    3. Mareel M,
    4. Fiers W,
    5. Van Roy F
    . Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell. 1991;66:107–119.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Thomas M,
    2. Kelly ED,
    3. Abraham J,
    4. Kruse M
    . Invasive lobular breast cancer: a review of pathogenesis, diagnosis, management, and future directions of early stage disease. Semin Oncol. 2019;46:121–132.
    OpenUrlCrossRefPubMed
  31. 31.↵
    1. Wass G,
    2. Clifford K,
    3. Subramaniam RM
    . Evaluation of the diagnostic accuracy of FAPI PET/CT in oncologic studies: systematic review and metaanalysis. J Nucl Med. 2023;64:1218–1224.
    OpenUrlAbstract/FREE Full Text
  32. 32.↵
    1. Alçın G,
    2. Arslan E,
    3. Aksoy T
    . 68Ga-FAPI-04 PET/CT in selected breast cancer patients with low FDG affinity a head-to-head comparative study. Clin Nucl Med. 2023;48:e420–e430.
    OpenUrl
  33. 33.↵
    1. Costa A,
    2. Kieffer Y,
    3. Scholer-Dahirel A,
    4. et al
    . Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell. 2018;33:463–479.e10.
    OpenUrlCrossRefPubMed
  • Received for publication October 4, 2023.
  • Revision received January 11, 2024.
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