Joint EANM-SNMMI guideline on the role of 2-[18F]FDG PET/CT in no special type breast cancer : (endorsed by the ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA).

INTRODUCTION: There is much literature about the role of 2-[18F]FDG PET/CT in patients with breast cancer (BC). However, there exists no international guideline with involvement of the nuclear medicine societies about this subject. PURPOSE: To provide an organized, international, state-of-the-art, and multidisciplinary guideline, led by experts of two nuclear medicine societies (EANM and SNMMI) and representation of important societies in the field of BC (ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA). METHODS: Literature review and expert discussion were performed with the aim of collecting updated information regarding the role of 2-[18F]FDG PET/CT in patients with no special type (NST) BC and summarizing its indications according to scientific evidence. Recommendations were scored according to the National Institute for Health and Care Excellence (NICE) criteria. RESULTS: Quantitative PET features (SUV, MTV, TLG) are valuable prognostic parameters. In baseline staging, 2-[18F]FDG PET/CT plays a role from stage IIB through stage IV. When assessing response to therapy, 2-[18F]FDG PET/CT should be performed on certified scanners, and reported either according to PERCIST, EORTC PET, or EANM immunotherapy response criteria, as appropriate. 2-[18F]FDG PET/CT may be useful to assess early metabolic response, particularly in non-metastatic triple-negative and HER2+ tumours. 2-[18F]FDG PET/CT is useful to detect the site and extent of recurrence when conventional imaging methods are equivocal and when there is clinical and/or laboratorial suspicion of relapse. Recent developments are promising. CONCLUSION: 2-[18F]FDG PET/CT is extremely useful in BC management, as supported by extensive evidence of its utility compared to other imaging modalities in several clinical scenarios.

Good clinical practice recommendations for the use of PET/CT in oncology.

Positron emission tomography/computed tomography (PET/CT) is a nuclear medicine functional imaging technique with proven clinical value in oncology. PET/CT indications are continually evolving with fresh advances made through research. French practice on the use of PET in oncology was framed in recommendations based on Standards-Options-Recommendations methodology and coordinated by the French federation of Comprehensive Cancer Centres (FNLCC). The recommendations were originally issued in 2002 followed by an update in 2003, but since then, a huge number of scientific papers have been published and new tracers have been licenced for market release. The aim of this work is to bring the 2003 version recommendations up to date. For this purpose, a focus group was set up in collaboration with the French Society for Nuclear Medicine (SFMN) to work on developing good clinical practice recommendations. These good clinical practice recommendations have been awarded joint French National Heath Authority (HAS) and French Cancer Institute (INCa) label status-the stamp of methodological approval. The present document is the outcome of comprehensive literature review and rigorous appraisal by a panel of experts, organ specialists, clinical oncologists, surgeons and imaging specialists. These data were also used for the EANM referral guidelines.

Tumor metabolism assessed by FDG-PET/CT and tumor proliferation assessed by genomic grade index to predict response to neoadjuvant chemotherapy in triple negative breast cancer.

PURPOSE: Survival is increased when pathological complete response (pCR) is reached after neoadjuvant chemotherapy (NAC), especially in triple-negative breast cancer (TNBC) patients. Positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (FDG) and the genomic grade index (GGI), each separately, showed good potential to predict pCR. Our study was designed to evaluate the predictive value for the therapeutic response of a combination of parameters based on FDG-PET, histoclinical features and molecular markers of proliferation. METHODS: Molecular parameters were measured on pre-treatment biopsy. Tumor metabolic activity was measured using two PET/CT scans, one before and one after 2 cycles of NAC. The pCR was determined on specimen after NAC. Event-free survival (EFS) was estimated using the Kaplan Meier method. RESULTS: Of 55 TNBC patients, 19 (35%) reached pCR after NAC. Tumor grade and Ki67 were not associated with pCR whereas GGI (P = 0.04) and its component KPNA2 (P = 0.04) showed a predictive value. The change of FDG uptake between PET1 and PET2 (ΔSUVmax) was highly associated with pCR (P = 0.0001) but the absolute value of baseline SUVmax was not (P = 0.11). However, the AUC of pCR prediction increased from 0.63 to 0.76 when baseline SUVmax was combined with the GGI (P = 0.016). The only two parameters associated with EFS were ΔSUVmax (P = 0.048) and pathological response (P = 0.014). CONCLUSIONS: The early tumor metabolic change during NAC is a powerful parameter to predict pCR and outcome in TNBC patients. The GGI, determined on pretreatment biopsy, is also predictive of pCR and the combination GGI and baseline SUVmax improves the prediction.

18FDG-PET/CT for predicting the outcome in ER+/HER2- breast cancer patients: comparison of clinicopathological parameters and PET image-derived indices including tumor texture analysis.

BACKGROUND: This study investigated the value of some clinicopathological parameters and 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography (18FDG-PET/CT) indices, including textural features, to predict event-free survival (EFS) in estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) locally advanced breast cancer (BC) patients. METHODS: FDG-PET/CT indices and clinicopathological parameters were assessed before neoadjuvant chemotherapy (NAC). After completion of chemotherapy, all patients had breast surgery with axillary lymph node dissection, followed by radiation therapy and endocrine therapy for 5 years. EFS was estimated using the Kaplan-Meier method. A Cox proportional hazard regression model was used for multivariate analysis. RESULTS: One hundred forty-three consecutive patients with stage II-III ER+/HER2- BC and without distant metastases at baseline PET were included. High standardized uptake values (SUVs), were associated with shorter EFS (HR = 3.51, P < 0.01 for SUVmax; HR = 2.76, P = 0.02 for SUVmean; and HR = 4.40 P < 0.01 for SUVpeak). Metabolically active tumor volume (MATV, HR = 3.47, P < 0.01) and total lesion glycolysis (TLG, HR = 3.10, P < 0.01) were also predictive of EFS. Homogeneity was not predictive (HR = 2.27, P = 0.07) and entropy had weak prediction (HR = 2.89, P = 0.02). Among clinicopathological parameters, EFS was shorter in progesterone receptor (PR)-negative tumor (vs. PR-positive tumor; HR = 3.25, P < 0.01); histology was predictive of EFS (lobular vs. ductal invasive carcinoma; HR = 3.74, P = 0.01) but not tumor grade (grade 3 vs. grade 1-2; HR = 1.64, P = 0.32). Pathological complete response after NAC was not correlated to the risk of relapse. Three parameters remained significantly associated with EFS in multivariate analysis. MATV (HR = 1.01, P < 0.01), progesterone receptor expression (HR = 2.90, P = 0.03) and tumor histology (HR = 3.80, P = 0.02). CONCLUSIONS: Baseline PET parameters measured before neoadjuvant treatment have prognostic values in ER+/HER2- locally advanced breast cancer patients. After multivariate analysis, metabolically active tumor volume remains significant while textural analysis of PET images is not of added value. Considering histopathological parameters, our study shows that patients with PR-negative or lobular invasive tumor have poorer prognosis than patients with PR-positive or ductal carcinoma, respectively.

Correlation between tumour characteristics, SUV measurements, metabolic tumour volume, TLG and textural features assessed with 18F-FDG PET in a large cohort of oestrogen receptor-positive breast cancer patients.

PURPOSE: The study was designed to evaluate 1) the relationship between PET image textural features (TFs) and SUVs, metabolic tumour volume (MTV), total lesion glycolysis (TLG) and tumour characteristics in a large prospective and homogenous cohort of oestrogen receptor-positive (ER+) breast cancer (BC) patients, and 2) the capability of those parameters to predict response to neoadjuvant chemotherapy (NAC). METHODS: 171 consecutive patients with large or locally advanced ER+ BC without distant metastases underwent an 18F-FDG PET examination before NAC. The primary tumour was delineated with an adaptive threshold segmentation method. Parameters of volume, intensity and texture (entropy, homogeneity, contrast and energy) were measured and compared with tumour characteristics determined on pre-treatment breast biopsy (Wilcoxon rank-sum test). The correlation between PET-derived parameters was determined using Spearman's coefficient. The relationship between PET features and pathological findings was determined using the Wilcoxon rank-sum test. RESULTS: Spearman's coefficients between SUVmax and TFs were 0.43, 0.24, -0.43 and -0.15 respectively for entropy, homogeneity, energy and contrast; they were higher between MTV and TFs: 0.99, 0.86, -0.99 and -0.87. All TFs showed a significant association with the histological type (IDC vs. ILC; 0.02 < P < 0.03) but didn't with immunohistochemical characteristics. SUVmax and TLG predicted the pathological response (P = 0.0021 and P = 0.02 respectively); TFs didn't (P: 0.27, 0.19, 0.94, 0.19 respectively for entropy, homogeneity, energy and contrast). CONCLUSIONS: The correlation of TFs was poor with SUV parameters and high with MTV. TFs showed a significant association with the histological type. Finally, while SUVmax and TLG were able to predict response to NAC, TFs failed.

¹8F-FDG PET/CT in the early prediction of pathological response in aggressive subtypes of breast cancer: review of the literature and recommendations for use in clinical trials.

Early assessment of response to neoadjuvant chemotherapy (NAC) might be helpful in avoiding the toxicity of ineffective chemotherapy and allowing refinement of treatment. We conducted a review of the literature regarding the applicability of (18)F-FDG PET/CT to the prediction of an early pathological response in different subgroups of breast cancer. Clinical research in this field has intensified in the last few years. Early studies by various groups have shown the potential of (18)F-FDG PET/CT in the early assessment of response to NAC. However, interim PET/CT in breast cancer has not yet gained wide acceptance compared to its use in other settings such as lymphomas. This is in part due to a lack of consensus that early evaluation of response can be used to direct change in therapy in the neoadjuvant breast cancer setting, and only limited data showing that response-adaptive therapy leads to improved outcomes. However, one major element that has hampered the use of (18)F-FDG PET/CT in directing neoadjuvant therapy is its evaluation in populations with mixed subtypes of breast cancer. However, major improvements have occurred in recent years. Pilot studies have highlighted the need for considering breast cancer subtype and the type of treatment, and have offered criteria for the use of PET/CT for the early prediction of response in specific settings. (18)F-FDG PET/CT has considerable potential for the early prediction of pathological complete response to NAC in aggressive subtypes such as triple-negative or HER2-positive breast cancers. The results of a multicentre trial that used early metabolic response on (18)F-FDG PET/CT as a means to select poor responders to adapt neoadjuvant treatment have recently been published. Other trials are ongoing or being planned.

Early Metabolic Response to Neoadjuvant Treatment: FDG PET/CT Criteria according to Breast Cancer Subtype.

PURPOSE: To investigate parameters based on fluorine 18 fluorodeoxyglucose (FDG) positron emission tomographic (PET) imaging that are best correlated with pathologic complete response (PCR) in human epidermal growth factor receptor type 2 (HER2)-positive cancer and triple-negative breast cancer (TNBC) and with partial or complete response in ER-positive/HER2-negative breast cancer. MATERIALS AND METHODS: This study was approved by institutional review board with waivers of informed written consent and included consecutive patients treated by neoadjuvant chemotherapy. Five PET examination-derived parameters were tested: standard uptake value (SUV) maximum (SUV(max)), peak (SUV(peak)), and mean (SUV(mean)), metabolically active tumor volume, and total lesion glycolysis (TLG). Absolute values at baseline PET, at PET imaging after two cycles of chemotherapy, and variation (ie, change) were measured. Correlations with pathologic response (Wilcoxon rank-sum test) and predictive power assessed (area under the curve [AUC] on the basis of receiver operating characteristic analysis) were examined. RESULTS: Included were 169 consecutive patients (mean age, 50 years). PCR was more frequent in HER2-positive tumors (16 of 33 patients [48.5%]) and TNBCs (20 of 54 patients [37%]) than in ER positive/HER2-negative tumors (four of 82 [4.9%]) (P < .001). Among patients with ER-positive/HER2-negative cancers, 33 patients had partial response. In TNBC, best association with PCR was obtained with change in SUV(max) (AUC, 0.86) or change in TLG (AUC, 0.88). In HER2-positive phenotype, absolute SUV(max) (or SUV(peak)) values at PET imaging after two cycles of chemotherapy (AUC for each cycle, 0.93) were better correlated with PCR than change in SUV(max) (AUC, 0.78; P = .11) or change in TLG (AUC, 0.62; P = .005). Regarding ER-positive/HER2-negative cancers, change in SUV(max) or change in TLG (AUC, 0.75) were parameters best correlated with partial or complete response. Baseline SUV(max) was higher in lymph nodes than in primary tumor in 31 patients. Findings were similar considering the site with highest FDG uptake. CONCLUSION: Quantitative indexes of tumor glucose use that are best correlated with pathologic response vary by phenotype: change in SUV(max) or TLG are most adequate for TNBCs and ER-positive/ HER2-negative cancers and absolute SUV(max) after two cycles of chemotherapy for HER2-positive breast cancers.

Do clinical, histological or immunohistochemical primary tumour characteristics translate into different (18)F-FDG PET/CT volumetric and heterogeneity features in stage II/III breast cancer?

PURPOSE: The aim of this retrospective study was to determine if some features of baseline (18)F-FDG PET images, including volume and heterogeneity, reflect clinical, histological or immunohistochemical characteristics in patients with stage II or III breast cancer (BC). METHODS: Included in the present retrospective analysis were 171 prospectively recruited patients with stage II/III BC treated consecutively at Saint-Louis hospital. Primary tumour volumes were semiautomatically delineated on pretreatment (18)F-FDG PET images. The parameters extracted included SUVmax, SUVmean, metabolically active tumour volume (MATV), total lesion glycolysis (TLG) and heterogeneity quantified using the area under the curve of the cumulative histogram and textural features. Associations between clinical/histopathological characteristics and (18)F-FDG PET features were assessed using one-way analysis of variance. Areas under the ROC curves (AUC) were used to quantify the discriminative power of the features significantly associated with clinical/histopathological characteristics. RESULTS: T3 tumours (>5 cm) exhibited higher textural heterogeneity in (18)F-FDG uptake than T2 tumours (AUC <0.75), whereas there were no significant differences in SUVmax and SUVmean. Invasive ductal carcinoma showed higher SUVmax values than invasive lobular carcinoma (p = 0.008) but MATV, TLG and textural features were not discriminative. Grade 3 tumours had higher FDG uptake (AUC 0.779 for SUVmax and 0.694 for TLG), and exhibited slightly higher regional heterogeneity (AUC 0.624). Hormone receptor-negative tumours had higher SUV values than oestrogen receptor-positive (ER-positive) and progesterone receptor-positive tumours, while heterogeneity patterns showed only low-level variation according to hormone receptor expression. HER-2 status was not associated with any of the image features. Finally, SUVmax, SUVmean and TLG significantly differed among the three phenotype subgroups (HER2-positive, triple-negative and ER-positive/HER2-negative BCs), but MATV and heterogeneity metrics were not discriminative. CONCLUSION: SUV parameters, MATV and textural features showed limited correlations with clinical and histopathological features. The three main BC subgroups differed in terms of SUVs and TLG but not in terms of MATV and heterogeneity. None of the PET-derived metrics offered high discriminative power.

Quarter-Century Transformation of Oncology: Positron Emission Tomography for Patients with Breast Cancer.

PET radiotracers have become indispensable in the care of patients with breast cancer. 18F-fluorodeoxyglucose has become the preferred method of many oncologists for systemic staging of breast cancer at initial diagnosis, detecting recurrent disease, and for measuring treatment response after therapy. 18F-Sodium Fluoride is valuable for detection of osseous metastases. 18F-fluoroestradiol is now FDA-approved with multiple appropriate clinical uses. There are multiple PET radiotracers in clinical trials, which may add utility of PET imaging for patients with breast cancer in the future. This article will describe the advances during the last quarter century in PET for patients with breast cancer.

Estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast tumors: early prediction of chemosensitivity with (18)F-fluorodeoxyglucose positron emission tomography/computed tomography during neoadjuvant chemotherapy.

BACKGROUND: The objective of this prospective study was to evaluate the ability of (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) to predict chemosensitivity in patients with estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. METHODS: Sixty-four consecutive patients underwent (18)F-FDG PET/CT scanning at baseline and after the second course of neoadjuvant chemotherapy (NAC). The evolution (Δ) between the 2 scans of image parameters (maximum standardized uptake value [SUV(max)], SUV(mean), metabolic tumor volume, and total lesion glycolysis [TLG]) was measured. Correlations between early changes in PET-derived parameters and pathologic response observed in surgical specimens after the completion of 8 courses of NAC were estimated with Mann-Whitney U tests. Response prediction on the basis of clinical data, histologic type, or molecular markers also was assessed (Fisher exact test). Receiver operating characteristic (ROC) analysis was used to compare the area under the curve (AUC) of each parameter. RESULTS: The best prediction of chemosensitivity was obtained with ΔTLG (-49% ± 31% in nonresponders vs -73% ± 25% in responders; P < .0001). Among the biologic parameters, only negative progesterone receptor status (57% responders vs 31% nonresponders; P = .04) and luminal B subtype (63% responders vs 22% nonresponders; P = .02) were predictive of a pathologic response. ROC analysis resulted in an AUC of 0.81, 0.73, 0.71, and 0.63 for ΔTLG, ΔSUV(max), luminal subtype, and progesterone receptor status, respectively. CONCLUSIONS: When patients responded to NAC, the majority of ER-positive/HER2 negative tumors exhibited partial tumor shrinkage; and the PET parameters that combined volume and activity measurements, such as TLG, offered better accuracy for early prediction than the SUV(max). Negative progesterone receptor status and luminal B subtype had weaker predictive power than PET-derived parameters.

Performance of FDG PET/CT in the clinical management of breast cancer.

In this analysis, the role of metabolic imaging with fluorine 18 fluorodeoxyglucose (FDG) in breast cancer is reviewed. The analysis was limited to recent works by using state-of-the-art positron emission tomography (PET)/computed tomography (CT) technology. The strengths and limitations of FDG PET/CT are examined in various clinical settings, and the following questions are answered: Is FDG PET/CT useful to differentiate malignant from benign breast lesions? Can FDG PET/CT replace sentinel node biopsy for axillary staging? What is the role of FDG PET/CT in initial staging of inflammatory or locally advanced breast cancer? What is the role of FDG PET/CT in initial staging of clinical stage IIA and IIB and primary operable stage IIIA breast cancer? How does FDG PET/CT compare with conventional techniques in the restaging of cancer in patients who are suspected of having disease recurrence? What is the role of FDG PET/CT in the assessment of early response to neoadjuvant therapy and of response to therapy for metastatic disease? Some recommendations for clinical practice are given.

Breast Cancer Systemic Staging (Comparison of Computed Tomography, Bone Scan, and 18F-Fluorodeoxyglucose PET/Computed Tomography).

After an overview of the principles of bone scintigraphy, contrast-enhanced computed tomography (CE-CT) and 18F-fluorodeoxyglucose (FDG)-PET/CT, the advantages and limits of these modalities in the staging of breast cancer are discussed in this paper. CT and PET/CT are not optimal for delineating primary tumor volume, and PET is less efficient than the sentinel node biopsy to depict small axillary lymph node metastases. In large breast cancer tumor, FDG PET/CT is useful to show extra-axillary lymph nodes. FDG PET/CT is superior to bone scan and CE-CT in detecting distant metastases, and it results in a change of treatment plan in nearly 15% of patients.

FDG-PET/CT for Primary Staging and Detection of Recurrence of Breast Cancer.

Breast cancer is the most frequent cancer diagnosed in women worldwide. Accurate baseline staging is necessary to plan optimal breast cancer management. Early detection and staging of recurrence are also essential for optimal therapeutic management. Hybrid FDG-PET/CT imaging offers high sensitivity in detecting extra axillary lymph nodes and distant metastases. Although FDG-PET/CT has some limitations for low proliferative tumors, low-grade tumors and for well-differentiated luminal breast cancer, PET/CT is useful for the initial staging of breast cancer, regardless of tumor phenotype (luminal, triple negative, or HER2+) and of tumor grade. Although FDG-PET/CT performs better for invasive ductal carcinoma (invasive carcinoma of no specific subtype), it is also helpful for staging invasive lobular carcinomas. At initial staging, FDG-PET/CT becomes very useful for staging from clinical stage IIB (T2N1 or T3N0). FDG-PET/CT could be useful in patients with clinical stage IIA (T1N1 or T2N0), but there is not enough strong evidence to recommend routine use in this subgroup. For clinical stage I (T1N0) patients, FDG-PET/CT offers no added value. In patients with recurrent breast cancer, FDG-PET/CT is more effective than conventional imaging in detecting locoregional or distant recurrence, whether suspected by clinical examination, conventional imaging, or elevation of a tumor marker (CA 15.3 or CEA). PET/CT is effective even in the presence of normal tumor markers. PET/CT is also a powerful imaging modality for performing a whole-body workup of a known recurrence and for determining whether or not the recurrence is isolated.

Negative Relationship between Post-Treatment Stromal Tumor-Infiltrating Lymphocyte (TIL) and Survival in Triple-Negative Breast Cancer Patients Treated with Dose-Dense Dose-Intense NeoAdjuvant Chemotherapy.

Background: Patients with triple-negative breast cancers (TNBC) have a poor prognosis unless a pathological complete response (pCR) is achieved after neoadjuvant chemotherapy (NAC). Few studies have analyzed changes in TIL levels following dose-dense dose-intense (dd-di) NAC. Patients and methods: From 2009 to 2018, 117 patients with TNBC received dd-di NAC at our institution. We aimed to identify factors associated with pre- and post-NAC TIL levels, and oncological outcomes relapse-free survival (RFS), and overall survival (OS). Results: Median pre-NAC and post-NAC TIL levels were 15% and 3%, respectively. Change in TIL levels with treatment was significantly correlated with metabolic response (SUV) and pCR. High post-NAC TIL levels were associated with a weak metabolic response after two cycles of NAC, with the presence of residual disease and nodal involvement at NAC completion. In multivariate analyses, high post-NAC TIL levels independently predicted poor RFS and poor OS (HR = 1.4 per 10% increment, 95%CI (1.1; 1.9) p = 0.014 and HR = 1.8 per 10% increment 95%CI (1.3−2.3), p < 0.0001, respectively). Conclusion: Our results suggest that TNBC patients with TIL enrichment after NAC are at higher risk of relapse. These patients are potential candidates for adjuvant treatment, such as immunotherapy, in clinical trials.