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Clinical Utility of PET/CT in Breast Cancer Management and Targeted Therapy

  • Xinzhong Hao
  • Xiaxia Meng
  • Zhifang Wu
Chapter
  • 525 Downloads

Abstract

Breast cancer is currently the most prevalent malignant disease affecting women’s health. Breast cancer is a highly heterogeneous tumor, comprising multiple entities associated with distinctive histological and biological features, clinical presentations, and responses to therapy. In addition to traditional treatment approaches, such as surgery, radiotherapy, endocrine therapy, and chemotherapy, targeted therapy is another emerging approach for breast cancer treatment. With the breakthrough in molecular biology and pharmacology research, new targeted drugs have been continuously applied in clinic and have achieved good clinical results.

2.1 Introduction

Breast cancer is currently the most prevalent malignant disease affecting women’s health. Breast cancer is a highly heterogeneous tumor, comprising multiple entities associated with distinctive histological and biological features, clinical presentations, and responses to therapy. In addition to traditional treatment approaches, such as surgery, radiotherapy, endocrine therapy, and chemotherapy, targeted therapy is another emerging approach for breast cancer treatment. With the breakthrough in molecular biology and pharmacology research, new targeted drugs have been continuously applied in clinic and have achieved good clinical results.

2.1.1 Epidemiology

Breast cancer is the leading cause of cancer-related death for women in both developed and developing countries [1]. In 2012, 1.7 million women were diagnosed with breast cancer, and 522,000 died from it at the same year [1]. From 1989 to 2012, breast cancer death rates decreased by 36% in the United States [2]. But in China, the incidence of breast cancer is still slowly rising [3].

According to the study by Lei Fan [3] from China, breast cancer is now still the most common cancer in Chinese women. With more than 1.6 million people are diagnosed with breast cancer and 1.2 million people die every year in China, accounts for 12.2% of all newly diagnosed cancers and 9.6% of all cancer deaths worldwide [3]. There is still a long way for China in the prevention and treatment of breast cancer.

There are regional differences in the incidence of breast cancer, and urban areas are higher than rural areas. The average age at diagnosis of breast cancer in China is 45–55 years old, younger than Western women.

Some risk factors are thought to contribute to the development of breast cancer. Currently, recognized risk factors include early age at first menstruation, late childbearing or not at all, older age, prior history of breast cancer, family history, obesity, lack of physical exercise, drinking alcohol, smoking tobacco, hormone replacement therapy during menopause, and ionizing radiation. Genes are also thought to be a major factor in 5–10% of cases [4], including BRCA1 and BRCA2, among others.

2.1.2 Molecular Subtypes and Gene Expression Tests in Breast Cancer

Most of the malignant breast tumors are adenocarcinomas, usually called as breast cancer. Breast cancer is a highly heterogeneous tumor, comprising distinctive entities associated with its own clinical, histological, molecular, and genic characteristics.

At the gross histopathology level, breast cancer can be divided into carcinoma in situ, and invasive carcinoma depended on whether tumor breaks through the basement membrane or not. According to the growth location of tumors in the breast, it can be divided into ductal carcinoma and lobular carcinoma (such as intralobular carcinoma in situ, ductal carcinoma in situ).

In clinic, infiltrating ductal carcinomas are most common, accounting for 70–80% of invasive breasts, followed by infiltrating lobular carcinoma accounting for 5–10%. In addition, there are some rare types of invasive breast cancer histology, such as tubular, mucinous, and medullary carcinoma. Compared with infiltrating ductal carcinomas, infiltrating lobular carcinomas tend to be multicentric and/or bilateral. Inflammatory breast cancer and Paget’s disease are two specific types of breast cancer, with particularly pathological and clinical features.

Over the years, new molecular diagnostic technology have been studied, which aims to find new biomarkers to better describe and distinguish entities. The development of new biomarkers provides clinicians with a reference for diagnosis of breast cancer, risk stratification, staging, treatment options, and finally helps to achieve precise and individualized treatment for patients.

According to the characteristics of immunohistochemistry (IHC), breast cancer can be divided into three major subtypes: tumors expressing the estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2) breast cancer. The remaining group is commonly referred to as triple-negative breast cancer (TNBC) due to lack of expression of ERs, PRs, and HER2. TNBC itself contains many different entities that have been identified through gene expression tests.

The seminal discovery of breast cancer research over the last two decades was the description of the intrinsic breast cancer subtypes. Perou et al. [5] analyzed gene expression patterns of breast cancer employing microarray-based gene expression profiling, identifying four major intrinsic gene signatures: luminal, triple-negative/basal-like, HER2-positive-enriched, and normal-like. Subsequent studies led to subdivision of luminal tumors into luminal A and luminal B subgroups. Table 2.1 demonstrates the classification of these subtypes and the specific immunohistochemical expression patterns [6].
Table 2.1

Breast cancer intrinsic subtypes with prevalent immunohistochemical profiles [6]

Intrinsic subtype

Immunohistochemistry

Luminal A

ER- and/or PR-positive, HER2-negative with Ki-67 < 14%

Luminal B

ER- and/or PR-positive, HER2-negative with Ki-67 ≥ 14%

ER- and/or PR-positive, HER2-positive with any Ki-67

HER2-enriched

ER- and PR-negative, HER2-positive

Basal-like

ER- and PR-negative, HER2-negative

Of mammary carcinogenesis, perhaps the most extensively studied are BRCA1, BRCA2, and TP53 genes. These are associated with a high risk of developing breast cancer in carriers, and hence they are referred to as high penetrance genes. However, it should be noted that among breast cancer patients with a strong family history, only 40% are thought to be caused by the above three genes [7]. This suggests that in the remaining 60% of cases, apart from sporadic breast cancers, other genetic pathways are likely involved.

In recent years, five novel gene expression prognostic tests [8] for breast cancer have been developed: MammaPrint, MapQuant Dx, Oncotype DX, PAM50, and Theros Breast Cancer Index. The development of multigene-based prognostic tests is not only to add prognostic and predictive information to conventional biomarkers but to provide more reliable and reproducible techniques than the IHC-based assays, which in turn reduces the technical errors and subjective interpretation [9].

In spite of their demonstrated efficacy, there are still large regional differences in the application of these tests, probably reflecting variations in economies, health systems, and physician training. Therefore, in many hospitals, immunohistochemical evaluation remains the primary method for the classification of breast cancer.

2.1.3 Targeted Therapy for Breast Cancer

Targeted therapy is a new treatment method in addition to the four traditional treatments of surgery, radiotherapy, endocrine therapy, and chemotherapy. With the deepening of pharmacology and molecular biology research, many molecular targets have been identified, and breakthroughs have also been made in the research and application of new targeted drugs.

Generally, according to the mechanism of action, targeted drugs can be classified into two categories. One of the categories acts on tumor cells, such as antihuman epidermal growth factor receptor 2 (HER2), PI3K/AKT/mTOR inhibitor, CDK4/6 inhibitor, and Poly (ADP-ribose) polymerase (PARP) inhibitor. Another category acts on the microenvironment, such as angiogenesis inhibitors.

2.1.3.1 Anti-HER2 Targeted Therapy

Human epidermal growth factor receptor 2 (HER-2) is not expressed in normal tissues but is overexpressed in tumor tissues. Twenty to thirty percent of breast cancer patients found HER-2 gene overexpression, and the high expression of HER-2 is closely related to the occurrence, development, prognosis, and metastasis of breast tumors. This type of breast cancer is usually highly invasive and has a poor prognosis.

According to the molecular mechanism, drugs targeting HER2 are mainly divided into three categories: Category 1 is a monoclonal antibody, including trastuzumab and pertuzumab, which specifically binds to the extracellular region IV or II of the HER2 receptor and inhibits HER2 receptor activation; Category 2 is a small molecule tyrosine-kinase inhibitor, representing the drug lapatinib, which reversibly interacts with the epidermal growth factor receptor (EGFR) and adenosine triphosphate (ATP) site of HER2 receptor tyrosine kinase regions and inhibit its tyrosine kinase activity; Category 3 is a monoclonal antibody. The representative drug is an antibody-conjugated drug, such as trastuzumab emtansine (TDM1), which is a combination of trastuzumab and anti-tubulin chemotherapeutic drugs through a disulfide bond. It can selectively bring chemotherapeutic drugs into cancer cells and enhance the induction of cancer cell apoptosis.

Numerous studies have shown that trastuzumab is the basic treatment for HER2-positive breast cancer, whether using trastuzumab alone or in combination with chemotherapy drugs, it can bring survival benefits to patients. However, in clinical practice, 70% HER2-positive breast cancer is resistant to trastuzumab, and almost all patients are relayed for resistance during treatment [10]. How to overcome trastuzumab resistance has become a key issue to be addressed in anti-HER2 targeted therapy.

Several large clinical studies have demonstrated that trastuzumab combined with chemotherapy can reduce the risk of disease recurrence and death in patients with HER2-positive early breast cancer, significantly improving patient outcomes.

2.1.3.2 Anti-angiogenic Targeted Therapy

Angiogenesis is the main cause of tumor growth and metastasis. Therefore, the treatment of targeted angiogenesis is also one of the important strategies. Currently, anti-angiogenic drugs for breast cancer include bevacizumab (targeting vascular endothelial growth factor, VEGF), ramucirumab (targeting vascular endothelial growth factor receptor 2, VEGFR 2), and multiple target of sorafenib and sunitinib. The application of anti-angiogenic targeted drugs in the treatment of advanced breast cancer is controversial. The treatment of anti-angiogenic targeted drugs in breast cancer needs to be further explored. In the future, it is necessary to find a therapeutic target and optimize the benefit population.

2.1.3.3 PI3K/AKT/mTOR Pathway Inhibitor

The PI3K/AKT/mTOR pathway plays an important role in the development of breast cancer. On the one hand, it is downstream of the HER2 pathway, and the activation of the PI3K/AKT/mTOR pathway is involved in the resistance mechanism of trastuzumab; on the other hand, it also interacts with the estrogen receptor (ER) signaling pathway and is involved in the pathogenesis of endocrine therapy resistance.

Everolimus is an inhibitor of mTOR target protein, and a large number of studies have demonstrated that everolimus reverses the activity of the aromatase inhibitor by inhibiting the activity of the PI3K/AKT/mTOR pathway. For postmenopausal women with advanced breast cancer, patients with aromatase inhibitor treatment failure, use of other endocrine drugs in combination with everolimus will become a new strategy to reverse endocrine therapy resistance.

2.1.3.4 Other Targeted Therapy

There are still some other targeted drugs which had been developed, such as cell cycle inhibitors CDK4/6 and PARP inhibitors. CDK4/6 is a representative cell cycle blocker. Phase II study showed that the CDK4/6 inhibitor palbociclib combined with letrozole versus single-agent letrozole for the treatment of postmenopausal ER-positive, HER2-negative advanced breast cancer patients, PFS significantly benefited (20.2 month vs 10.2 months, P < 0.001) [11]. In 2015, the FDA approved palbociclib combined with letrozole as an initial regimen for the treatment of postmenopausal ER-positive, HER2-negative advanced breast cancer. For postmenopausal women with advanced breast cancer, patients who failed aromatase inhibitor therapy, use of other endocrine drugs in combination with everolimus will become a new strategy to reverse endocrine therapy resistance.

PARP mainly affects the repair of damaged DNA, resulting in the accumulation of damaged DNA, and ultimately induces tumor cell apoptosis. Currently, iniparib, olaparib, and veliparib are representatives of PARP inhibitors and are undergoing relevant clinical trials.

With the development of molecular biology, breast cancer has entered the era of targeted therapy. As new targeted drugs continue to be developed, prospective studies are needed to determine predictive outcomes, further optimizing the benefit population and maximizing the efficacy of targeted therapy.

2.2 Clinical Utility of 18F-FDG PET/CT in Breast Cancer

The application of PET/CT has been extensively studied in the management of patients with breast cancer, but not applied as a clinical routine in the diagnosis of primary breast cancer. PET/CT cannot replace the sentinel node biopsy in the diagnosis of breast cancer clinically. However, for the detection of supraclavicular, mediastinal, and internal mammary metastatic lymph nodes, PET/CT performs better than other imaging methods. Lymph nodes in these areas may be easily missed in routine CT and MRI study. In the detection of distant metastases, PET/CT has a better accuracy in detecting lytic bone metastases compared to bone scintigraphy. PET/CT is recommended in clinic when advanced-stage disease is suspected and conventional modalities are inconclusive. For the monitoring of locoregional recurrence, PET/CT has a high sensitivity and specificity. Numerous studies support the role of PET/CT in prediction of response to neoadjuvant radiation or chemotherapy. With further research on the treatment planning and evaluation of patients with breast cancer, the role of PET/CT can be further extended.

2.2.1 The Heterogeneity and 18F-FDG Uptake in Breast Cancer

Breast cancer is a highly heterogeneous tumor disease. It is well-known that the glycolysis activity of tumor cells affects 18F-FDG uptake. In general, glycolytic rates of cancer cells are correlated with HIF-1a and c-Myc expression resulting in considerable variability in glycolytic activity. Researches have already shown that the extent of 18F-FDG uptake in breast cancer is affected by a variety of factors.

A larger primary tumor, a positive axillary lymph node status, and higher TNM stage were all significantly associated with a higher SUVmax [12]. The uptake of 18F-FDG is also correlative with the pathological types and cell phenotype of breast cancer. Infiltrating ductal carcinoma has higher 18F-FDG uptake than infiltrating lobular carcinoma even for the same size tumors. The higher 18F-FDG accumulation also correlates with the higher histological grade and the higher expression of the proliferation marker Ki-67 [13, 14]. ER negativity, PR negativity, HER2 positivity, and high Ki-67 expression were also significantly correlated with a higher SUVmax. Basu et al. [15] and Kitajima et al. [12] found that tumors with a triple-negative phenotype had a higher FDG uptake. Breast cancers with a p53 mutation were repeatedly shown to be associated with poorer prognosis. Several studies [14, 16, 17] demonstrated the positive correlation between FDG uptake and p53 status, but another study by Buck A [18] showed that there was no correlation between these two indexes.

2.2.2 Detection and Differentiation of Primary Breast Cancer

Both mammography and ultrasound are most commonly used imaging methods in detection, differential diagnosis, the measurement of tumor size, and extent of breast cancer. MR has a high soft tissue resolution and has shown high sensitivity and specialty in the several aspects mentioned above. In addition, MR may find some additional breast cancer lesions, which may do not be displayed on other conventional imaging. Due to the many advantages of MR, it is increasingly being used in clinical practice.

18F-FDG PET/CT can be used for detection and visualization of the primary tumor. However, due to the limited resolution of PET scanners and the influence of some breast cancer pathological characteristics (e.g., low 18F-FDG uptake in high-grade cancer and/or in lobular cancer), PET has poor sensitivity for detection of small lesions. In a study by Avril et al. [19], while PET imaging detected 92% of pT2 lesions (>20 mm, but <50 mm) (see Fig. 2.1), only 68% of pT1 lesions (<20 mm) were detected. And 65% of lobular carcinomas had false-negative results, compared with ductal carcinomas (24% false-negative) [20]. Studies have also shown that FDG-PET has poor sensitivity for submillimeter breast cancer lesions, and the sensitivity of detection is less than 50% [21, 22]. As mentioned above, infiltrating lobular carcinoma is more likely to be missed.
Fig. 2.1

A 56-year-old woman with suspicious left lung adenocarcinoma (no increased activity) undergoing 18F-FDG PET/CT for tumor staging. An incidental 18F-FDG focus (black solid arrow) was seen in the upper and medial quadrant of the right breast on coronal maximum intensity projection (MIP) PET image and fuse imaging (white hollow arrow), pathologically confirmed as invasive ductal adenocarcinoma with a maximum diameter of 2.6 cm. No obvious abnormality was found at CT image (white solid arrow)

Positron emission mammography (PEM) is a breast-dedicated PET device, which with a high spatial resolution (even less than 2 mm) has showed promising results. It has dramatic improvements of sensitivity and specificity for detecting breast cancer lesions (especially for small lesions), compared to conventional whole-body PET. In the study of Kalinyak et al. [23], 109 primary invasive breast cancers (the average size 1.6 ± 0.8 cm) were enrolled. They found that the detection rates obtained with PEM and conventional PET/CT were 95% and 87%, respectively (p < 0.029). A meta-analysis [21] that evaluated eight studies comprising 873 breast lesions (the size ranged from 0.1 to 10 cm) showed a pooled sensitivity of 85% (95% CI, 83–88%) and a specificity of 79% (95% CI, 74–83%) on a lesion basis, using FDG PEM in women with suspected breast malignancy. Another report by Lima et al. [24] also showed similar results. A total of 80 lesions (the size ranged from 0.4 to 11.2 cm, mean 2.6 cm, included 76 breast cancers and 4 benign lesions) were enrolled; 63/76 breast cancer lesions was detected by PEM (the C-shape scanner); the lesion-based sensitivity was 83% (63/76), and this was increased to 90% (63/70) after excluding lesions outside the field of view.

A multicenter comparative study [25] determined the efficacy of PEM and DCE-MRI on ipsilateral pre-surgery planning, including 388 patients who undertook MRI and PEM, showed that a total of 116 malignant lesions were found after surgery, 61 of 116 malignant lesions (53%) were raised by MR for suspicious malignancy; 47 of these (41%) were raised as suspicious on PEM (P = 0.04), and only 24 lesions (21%) were raised as suspicious on conventional imaging. This result demonstrates that MR is superior to PEM in detecting breast cancer lesions.

Some benign lesions of the breast may also show the concentrated FDG uptake and sometimes are not easy to be differentiated from breast cancer. The following review will help us understand the uptake of breast lesions. The meta-analysis [26] reviewed the significance of incidental FDG uptake (from whole-body PET) in breast; the pooled risk of malignancy of incidental FDG uptake was 48% (95% CI, 38–58%), and the pooled risk of malignancy of incidental FDG uptake with histological examination was 60% (95% CI, 53–66%).

False-positive uptake caused by benign lesions had been reported, such as breast fibrocystic disease, fibroadenomas, papilloma, silicone leakage, fat necrosis, inflammatory, and infectious diseases. Breast fibrocystic disease usually does not exhibit very high FDG uptake, and higher FDG uptake generally indicates higher risk of malignancy. Lobulated contour, crab-like edge, ill-defined, and clustered granular calcification are typical morphological characteristics of breast cancer. In contrast-enhanced MR imaging, enhanced patterns of breast cancer, such as time-signal curves, contribute to the differentiation of benign diseases and breast cancer.

In addition, it has been reported that dual-time-point PET/CT imaging helps to increase the specificity and to better differentiate primary breast cancer from benign tumors or inflammatory processes [27, 28]. However, its usefulness has not yet been demonstrated in large series.

2.2.3 Initial Staging

Accurate and reliable initial staging is the premise for determining breast cancer treatment options and the basis for prognosis assessment. Once breast cancer is diagnosed, staging of the breast cancer must be performed. Currently, the TNM staging system (Tables 2.2 and 2.3) is widely used in clinic. Current evidence suggests that 18F-FDG PET/CT has a good performance for patients with clinical stage IIB and higher stage, and its performance is not affected by the breast cancer cell phenotype, tumor grade, and patient’s age.
Table 2.2

TNM staging system for breast cancer according to the AJCC cancer staging manual [29]

TNM category

Clinical data

Primary tumor

TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor ≤2 cm in greatest dimension

T2

Tumor >2 cm but not ≤5 cm in greatest dimension

T3

Tumor >5 cm in greatest dimension

T4

Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules)

T4a

Extension to the chest wall, not including only pectoralis muscle adherence/invasion

T4b

Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d’orange) of the skin, which do not meet the criteria for inflammatory carcinoma

T4c

Both T4a and T4b

T4d

Inflammatory carcinoma

Regional lymph nodes

NX

Regional lymph nodes cannot be assessed (e.g., previously removed)

N0

No regional lymph node metastasis

N1

Metastases to movable ipsilateral level I and II axillary lymph nodes

N2

Metastases in ipsilateral level I and II axillary lymph nodes that are clinically fixed or matted or in clinically detected ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastasesa

N3

Metastases in ipsilateral infraclavicular (level III axillary) lymph nodes with or without level I and II axillary lymph node involvement, or in clinically detected ipsilateral internal mammary lymph nodes with clinically evident level I and II axillary lymph node metastases, or metastases in ipsilateral supraclavicular lymph nodes with or without axillary or internal mammary lymph node involvementa

N3a

Metastases in ipsilateral infraclavicular lymph nodes

N3b

Metastases in ipsilateral internal mammary lymph nodes and axillary lymph nodes

N3c

Metastases in ipsilateral supraclavicular lymph nodes

Distant metastasis

M0

No distant metastasis

M1

Distant metastasis

aA clinically detected lymph node is defined as one detected by using imaging studies (excluding lymphoscintigraphy) or by using clinical examination and having characteristics highly suggestive of malignancy or a presumed pathologic macro-metastasis on the basis of results of fine-needle aspiration biopsy with cytological examination

Table 2.3

TNM stage grouping for breast cancer according to the AJCC cancer staging manual [29]

Stage

T category

N category

M category

0

Tis

N0

M0

IA

T1a

N0

M0

IB

T0

N1mi

M0

T1a

N1mi

M0

IIA

T0

N1b

M0

T1a

N1b

M0

T2

N0

M0

IIB

T2

N1

M0

T3

N0

M0

IIIA

T0

N2

M0

T1a

N2

M0

T2

N2

M0

T3

N1

M0

T3

N2

M0

IIIB

T4

N0

M0

T4

N1

M0

T4

N2

M0

IIIC

Any T

N3

M0

IV

Any T

Any N

M1

Note: N1mi nodal micrometastases

aT1 includes T1mi

bT0 and T1 tumors with nodal micrometastases only are excluded from stage IIA and are classified as stage IB

2.2.3.1 T Staging

The size of the tumor lesion, tumor’s relationship with the adjacent structure, and whether tumor are multicenter lesions are the important indicators for breast cancer T staging, which is an especially important consideration for planning of optimal breast conservation surgery.

Duo to the low spatial resolution of PET, PET remains inadequate for accurately defining the size and involved rang of breast cancer. To a certain extent, CT imaging in PET/CT can make up for this shortcoming. However, despite a high-density resolution of CT, small breast cancers (especially those in dense breasts) are often not well displayed by CT. When the breast cancer lesion grows to a certain size, CT can show its advantages in the measurement of lesion size and in judging the relationship between breast cancer and intercostal muscles and ribs.

US and mammography have relatively high sensitivity for the detection of small breast cancer lesions, high accuracy for measuring lesion size, and are easy to use and low in cost. But the size and extent of breast cancer are frequently underestimated by mammography and ultrasound.

MR can clearly display the contour of the lesion, so that accurate measurement of the lesion size can be performed, and determine the relationship between the lesion and the adjacent tissue. As it was reported in the study [28], FDG PET had less sensitivity than dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the determination of the delineation of the primary tumor and in screening for multifocality. Forty patients underwent PET/CT and DCE-MRI [28]; MR imaging aided classification of the T staging correctly in 77% of cases while PET/CT only in 54% of cases (P = 0.001).

Because of the high sensitivity of PEM, the T stage of breast cancer may be altered by the discovery of multicenter tumors and extensive intraductal breast cancer. A multicenter comparative study [25] on the effects of PEM and MR on ipsilateral presurgical planning, which included 388 patients who undertook DCE-MRI and PEM, showed that MR imaging had greater lesion-level sensitivity and detection accuracy for mastectomy. In total 89 women with breast cancer required more extensive surgery; only 41 (46%, 41/89) were identified with PEM (P = 0.003); 61 (69%, 61/89) were identified with MR imaging. From the above data, it can be seen that DCE-MRI is superior to PEM in the detection of intraductal infiltration and multicenter breast cancer.

2.2.3.2 Axillary Lymph Node Staging

Axillary lymph node status is an essential consideration; it affects clinical decision-making and prognosis of breast cancer. In recent years, sentinel lymph node biopsy (SLNB) has become widely accepted as a less invasive alternative to axillary lymph node dissection (ALND) and has become the standard procedure for patients with small primary breast cancers [20].

In a prospective multicenter study [30], FDG PET (without the CT component) was performed in 360 female patients with newly diagnosed invasive breast cancer. For detection of metastatic axillary nodal, the sensitivity and specificity of PET were, respectively, 61% and 80% [30]. Another meta-analysis also yielded similar results. In the meta-analysis [31], researchers evaluated the diagnostic accuracy of PET (with or without CT). Nineteen studies from PET (n = 1729) showed mean sensitivity was 66% (range, 50–79%), and mean specificity was 93% (range, 89–96%). Seven studies from PET/CT (n = 862) showed that mean sensitivity was 56% (range, 44–67%), mean specificity was 96% (range, 90–99%), and the mean sensitivity to micrometastases (≤2 mm) is 11% (5–22%) [31].

Although FDG PET/CT has a relatively high specificity in detecting axillary lymph node involvement but has less sensitivity, PET/CT cannot replace sentinel node biopsy in patients with breast cancer. In a study by Veronesi et al. [32] including 236 patients with clinically negative findings for axillary involvement, only 37% of patients with positive results of sentinel node biopsy had positive findings at PET [32].

18F-FDG uptake of axillary lymph nodes in the drainage area of breast cancer does not all mean metastasis, and there is a possibility of false-positive uptake. Such false positive was also mentioned in the study by Verones et al. [32] on the value of PET for axillary metastases. In all 43 patients with positive axillary lymph nodes on PET, 5 patients were confirmed to be nonmetastatic lymph nodes by surgical resection. This situation needs to be brought to the attention of nuclear medicine and clinical physicians. Reactive hyperplasia lymph nodes is the main cause of false-positive results, and their FDG uptake is often lower.

In addition to proliferative lymph nodes, FDG leakage at injection site is also the cause of false-positive uptake of axillary lymph nodes (because of the injection technology, FDG leaks into the subcutaneous tissue space at the injection site and is drained back to the axillary lymph nodes through the ipsilateral lymphatic vessels, resulting in increased FDG physiological uptake in these lymph nodes). For patients with unilateral breast cancer, it is suggested that intravenous injection of radiopharmaceuticals should be performed on the contralateral upper limb vessel, to reduce the interference of this physiological uptake in the diagnosis of axillary lymph node metastasis. Fundamentally, avoiding leakage of injection site through improving injection technology is the best choice to solve the problem.

Diagnostic performance of PET/CT for axillary lymph node metastasis does not seem to be superior to that of US or MRI. Ahn et al. [33] demonstrated that for detection of lymph node metastasis, the diagnostic accuracy of US was 78.8% and that of FDG-PET was 76.4%. As shown by the meta-analysis [34], for detection of lymph node metastasis, the mean sensitivity and specificity of gadolinium-enhanced MR was 88% (95% CI, 78%–94%) and 73% (95% CI, 63%–81%), respectively.

PET/CT was not able to reliably identify axillary lymph node involvement; it is not routinely recommended for axillary staging of patients with newly diagnosed breast cancer.

2.2.3.3 Staging in Stage II–III Disease and Inflammatory Breast Cancer

Axillary clearance is usually limited to Berg I and Berg II levels. Whether lymph nodes involvement at Berg level III (infraclavicular) or in extra-axillary local-regional nodes (such as supraclavicular or internal mammary) have important implications for clinical decision-making, especially in surgery and radiotherapy. Lymph node involvement in the axillary Berg level III area, in the supraclavicular area, or in the internal mammary area is classified as an N3 (stage IIIC) lesion according to the recently revised 8th edition of the AJCC Cancer Staging Manual [29]. Data from the national cancer institute database in 2001–2002 showed that women patients with stage IIIC disease had poor prognosis, and the 5-year survival rate was only 49%.

In a study [35] of 39 patients with stages II–III breast carcinoma, PET/CT successfully found 3 patients of extra-axillary lymph node involvement which were missed in conventional imaging method. According to the results of PET/CT, the extent of surgical dissection and radiation therapy fields were modified in all three patients. In another study [36], also involving patients with stages II-III breast carcinoma, radiation therapy planning was altered in seven patients with extra-axillary lymph node involvement (account for 12% of the total number of patients) not detected by US examination.

A prospective study from Groheux et al. [37] also reported the value of 18F-FDG PET/CT in the evaluation of breast cancer staging. A total of 131 consecutive patients were enrolled. They underwent physical examination, mammogram, ultrasound, and magnetic resonance imaging before the 18F-FDG PET/CT examination. Of these, 36 were classified as clinical stage IIA cancer, 48 were classified as clinical stage IIB, and 47 were classified as clinical stage IIIA cancer. 18F-FDG PET/CT results helped clinicians modify staging for 5.6% of patients with stage IIA cancer, for 14.6% of patients with stage IIB cancer, and for 27.6% of patients with stage IIIA cancer. Segaert [38] and Bourgeois [39], respectively, reported the value of preoperative PET/CT for stage IIB and IIIA breast cancer, similar results for locally advanced breast cancer had been obtained.

As for the patients with clinical IIB stage and more advanced stage breast cancer, PET/CT often provides critical information and is considered to be superior to conventional staging (see Fig. 2.2).
Fig. 2.2

A 31-year-old woman with breast cancer undergoing FDG PET/CT for tumor staging. Left internal mammary lymph nodes (thick solid arrow) are easily misdiagnosed as normal costal cartilage on CT image, but increased 18F-FDG activity (thick hollow arrow) was seen on fuse imaging. In addition, multiple enlarged lymph nodes with increased 18F-FDG activity can be seen in the left axillary (thin solid/hollow arrow)

Inflammatory breast cancer is a special and highly aggressive form of breast cancer, characterized by high rate of local recurrence, distant metastases, and mortality, which has the poorest prognosis among primary breast cancers. Most patients had axillary and/or supraclavicular lymph node metastases, almost 30% of patients have distant metastases at the time of diagnosis [40]. A study from Alberini [40] include 59 patients with inflammatory breast cancer, shown that the detection rate of PET/CT for primary tumors of inflammatory breast cancer was 100%. Three studies [40, 41, 42] have reported the value of PET for lymph node involvement in inflammatory breast cancer. PET found more metastatic lymph nodes than conventional images, with about 15–56% more.

PET/CT is useful for diagnosis of the lymph node metastases at extra-axillary sites, such as the internal mammary lymph nodes, subclavian lymph nodes, supraclavicular, and the intrathoracic lymph nodes. Whether these regional lymph nodes are involved or not will directly impact on the staging and the subsequent treatment strategies.

2.2.3.4 Distant Metastases of Breast Cancer

Currently, there is no evidence to prove that the use of PET/CT to further clarify distant metastases can benefit patients with ductal carcinoma in situ or clinical stage I or stage IIA.

The common distant metastatic sites of breast cancer are skeleton and lung, followed by lung, liver, brain, and ovary. Whether distant metastasis has occurred, there is a direct impact on the patient’s treatment planning and prognosis, and early definite diagnosis benefits disease outcome in patients.

Skeleton Metastases

Generally, according to the density difference between bone metastases and normal bone tissue at CT, bone metastases can be divided into osteolytic, osteogenic, and mixed types (both osteogenesis and osteolysis). At CT, there is another type of bone metastasis which is called invisible-type bone metastasis, which is not displayed because they do not cause visible bone destruction or osteogenic abnormality.

Bone scintigraphy is widely used in the detection of bone metastases, and it is a whole-body examination with relatively high sensitivity, especially those with active osteogenic activity. Bone scintigraphy sensitivity ranges from 62 to 100%, and its specificity is between 78 and 100% [43].

However, in some cases, it shows its disadvantage. The bone scintigraphy may present false negative for purely osteolytic bone metastases, and it may present false-positive uptake for some benign diseases, such as osteoporotic fracture, infectious diseases, arthritis, primary bone tumors, and tumor-like diseases.

SPECT/CT scanner equipped with simultaneous CT furtherly improves the specificity and the susceptibility, compared with those of conventional bone scintigraphy. However, the part of invisible-type metastases may still be missed in SPECT/CT examination. For the kind of metastasis, PET/CT have high sensitivity and specificity (see Fig. 2.3).
Fig. 2.3

A 58-year-old woman with right breast cancer (invasive ductal carcinoma) undergoing 18F-FDG PET/CT for tumor staging. PET/CT showed multiple bone and bilateral lung metastatic. A 18F-FDG focus was seen in transverse process of the third lumbar on coronal maximum intensity projection (MIP) PET image (black solid arrow) and fuse imaging (white hollow arrow), no clear abnormality was seen on axial CT images of the same site (white solid arrow)

Studies also suggest that 18F-FDG PET outperforms CT and bone scintigraphy in detection of invisible-type, osteolytic, and mixed bone metastases [44, 45, 46, 47]. But 18F-FDG PET may miss purely sclerotic metastases, which often contain fewer tumor cell. The additional anatomical information provided by the CT component of PET/CT often helps to improve sensitivity for the detection of purely sclerotic bone lesions (see Fig. 2.4).
Fig. 2.4

A 53-year-old woman with left breast cancer and multiple bone metastases. PET/CT showed multiple bone metastases. In sagittal CT images, metastatic lesions of the 11th thoracic spine demonstrated complete osteopetrosis (thick white arrow), no increased 18F-FDG uptake was observed (thick solid arrow). The remaining bone metastases also showed osteosclerosis with different degrees of increased 18F-FDG uptake (thin white/black arrows)

A study [46] for comparison of 18F-FDG PET/CT and bone scintigraphy for detection of bone metastases in breast cancer showed that the sensitivity of bone scintigraphy was 76% (53/70) compared to 96% (67/70) for 18F-FDG PET/CT.

18F-Fluoride is a highly sensitive bone-seeking PET tracer used for detection of skeletal abnormalities. With the popularization of PET/CT, 18F-NaF PET/CT bone scan is increasingly used clinically. 18F-NaF PET/CT has shown higher sensitivity for detection of bone metastases in breast cancer, compared to 99mTc-MDP SPECT bone scan. The sensitivity and specificity of 18F-NaF PET/CT in evaluating bone metastases were, respectively, 91% and 91% [48]. In addition, studies showed that combined 18F-FDG and 18F-NaF PET/CT was superior to 18F-FDG PET/CT alone for the detection of skeletal/marrow metastases in breast cancer [49, 50].

Extra-skeletal Metastases

The timely detection of pulmonary metastasis is important for accurate staging and assessing the likelihood of surgical clearance. CT is routinely performed on patients with higher risk of pulmonary metastases. Compared to standalone CT, the metabolic information provided by the 18F-FDG PET/CT can increase the specificity of the study and can facilitate the classification of suspicious indeterminate lesions, especially if they are more than 8 mm in diameter. Also, the reported physicians need to be alert to the potential risk of false-positive PET/CT findings mainly due to radiation pneumonitis, bacterial pneumonia, and granulomatous disease.

The physiological uptake of the liver limits the diagnostic accuracy of the PET/CT in detecting liver metastases. Adrenal metastatic lesions often show a very high 18F-FDG uptake; however, there are also a number of benign reasons leading to high 18F-FDG uptake of adrenal, such as stress, adrenal hyperplasia, adrenocortical adenoma, etc. Further confirmation is recommended. As for the diagnosis of brain metastases, the usefulness of 18F-FDG is seriously limited by the highly physiological uptake in the normal brain, especially in the cortex, enhanced MR should be a most choice.

2.2.4 Response Assessment

Traditional morphological imaging is mainly based on changes of the tumor size before and after treatment for response assessment. Different from traditional imaging, metabolic parameters in 18F-FDG PET is commonly used as an index of response evaluation, such as SUVmax, SUVlean, ΔSUVmax, total lesion glycolysis (TLG), metabolic tumor volume (MTV), etc. As we all know, changes in metabolic activity generally occur earlier than changes in tumor size; 18F-FDG PET as a metabolic and functional imaging can be used to evaluate early response of treatment.

2.2.4.1 Early Response Assessment

Early and reliable prediction of treatment response of the primary breast cancer may allow changing the treatment strategy in case of an ineffective therapy and decreasing unnecessary side effects.

Some results had shown a correlation between early changes in SUV (after one or two cycles of chemotherapy) and the histopathologic response at completion of chemotherapy. A study [51], including 66 patients with HER2-positive breast cancer, showed that ASUVmax in patients with pathologic complete response (pCR) had significantly greater reductions at weeks 2 and 6 (P = 0.02 for both time points), compared to SUVmax in those without a pCR. Mean SUVmax reductions were 54.3% versus 32.8% at week 2 and 61.5% versus 34.1% at week 6 for pCR and non-pCR.

The time of therapy assessment for NAC has an influence on the accuracy of response assessment. PET imaging has a better performance for the prediction of pathological response when it is performed after the second cycle of NAC. A multicenter study [52] including 104 patients (receiving one or two cycles of chemotherapy) shown pathologic nonresponders were identified with a negative predictive value of 90%, using a threshold of 45% decrease in SUV after the first cycle of chemotherapy. When using more than 55% reduction in SUV as the threshold after the second cycle, similar results is achieved [52]. Another study [53] showed, when using a threshold of 60% decrease in SUV, the sensitivity, specificity, and negative predictive value of FDG PET were 61%, 96%, and 68% after one cycle of NAC, 89%, 95%, and 85% after two cycles, and 88%, 73%, and 83% after three cycles, respectively. A subgroup study from a meta-analysis by Fangfang Tian [54] for response to neoadjuvant chemotherapy also has shown similar result. With pCR as the reference standard, 18F-FDG PET after two cycles and with at least a 50% reduction of the SUVmax as a threshold demonstrated the sensitivity of 85% (77–91%) and the specificity of 79% (69–86%).

For response assessment of breast cancer, there are following issues that need to be noted. Response assessment using 18F-FDG PET/CT is more meaningful for tumors with higher SUV. Low metabolic tumors may suggest resistance to chemotherapy. In the study by Schwarz-Dose [52], none of the 23 patients with initial SUV less than three achieved a complete histopathologic response.

2.2.4.2 Post-therapy Evaluation

Endocrine therapy has become an important part of systemic breast cancer therapy in women with ER-positive breast cancer. It should be noted that metabolic flares phenomenon may occur after endocrine therapy, which are manifested as sudden, aggravation of tumor-related symptoms and potential signs of disease progression in imaging, such as 18F-FDG avid lymphadenopathy. The metabolic flare phenomenon occurs usually after week 1 or 2 of endocrine therapy; it is caused by the initial agonist effect of tamoxifen and considered an effective sign of treatment [55].

Due to the limited data, the significance of 18F-PET/CT for the evaluation of response after the completion of treatment is not clear. The combination of PET and CT seems to be especially helpful in evaluating bone metastases. Additionally, to avoid false-negative interference caused by “metabolic stunning” of residual tissue, it is advised to wait at least 4–6 weeks after completion of the therapy. However, further multicenter studies need to be performed to deepen our understanding.

2.2.5 Monitoring Recurrence

Early detection of the extent and characters of recurrent disease can help clinician to adopt an optimal and reasonable treatment program and improve the prognosis of patients.

Clinical symptoms, biological markers (such as CA153, CEA), and routine radiological examination are commonly used methods to determine the recurrence of breast cancer. 18F-FDG PET/CT seems to perform better than routine imaging for detecting locoregional recurrence, especially the thoracic wall and extra-axillary lymph nodes, which are superior to CT and MR [56, 57, 58]. PET also has advantages in differentiating tumors from posttreatment scar or fibrosis, while it is often difficult to differentiate between them in conventional imaging.

A meta-analysis [59] showed that in breast cancer patients with elevated clinical tumor markers, the sensitivity, specificity, and accuracy of 18F-FDG PET for detecting recurrent tumors were 87.8%, 69.3%, and 82.8%, respectively.

18F-FDG PET/CT is superior to conventional imaging in the evaluation of disease relapse in breast cancer patients. A study by Champion, L [60], 187 true recurrences in 228 patients with increasing CA153 and/ or CEA were diagnosed by PET/CT. Compared with the standard work-up available in 67 patients with increasing tumor marker, PET/CT had a higher sensitivity and accuracy (94.5% vs 33% and 94% vs 48%, respectively). According to a study [57] including seven literatures, the sensitivity, specificity, and accuracy of the restaging of breast malignant tumors using PET/CT were, respectively, 85%–97%, 52%–100%, and 60%–98%. Two studies [61, 62] have also shown that PET/CT is more accurate in diagnosing breast cancer recurrence than enhanced CT or alone PET.

2.2.6 Prognostic Assessment

The prognosis of breast cancer is affected by many factors, such as pathological type, immunohistochemistry phenotype, tumor staging, and rationality of treatment.

Studies have shown that early response in patients receiving neoadjuvant chemotherapy before surgery is a good predictor for posttreatment response. In a study by Kenny [63], absence of response in the primary tumor at week 2 was predictive of nonresponse at week 6 (at least a 15% reduction of the SUVmax were considered responding), with a negative predictive value of 90% (18/20 patients). The presence of response at week 2 was predictive of response at week 6, with a positive predictive value of 78.5% (33/42 patients).

Based on the advantage of PET/CT staging, PET/CT can evaluate the prognosis of patients. One study [64] reported the value of PET/CT in evaluating the prognosis of patients with clinical II and stage III breast cancer. Sufficient follow-up was conducted for 189 patients with IIB and higher stages, and it was found that the 3-year disease-specific survival of patients with distant metastasis was significantly shorter than that of patients without distant metastasis (57% vs 88%, P < 0.001).

Several literatures reported that the degree of FDG uptake in primary tumor was of prognostic value. High FDG uptake was associated with poor outcome. In the study by Inoue et al. [65], FDG PET was performed preoperatively in 81 patients. With using SUV equal to 4.0 as the cutoff, the patients were randomly divided into the high SUV group and the low SUV group. Five-year disease-free survival rates in the high SUV group were significantly lower than that in the low SUV group (75.0% vs 95.1%, P = 0.011).

2.3 Clinical Application of 18F-Fluoroestradiol PET

18F-fluoroestradiol (18F-FES) is an estrogen receptor imaging agent, targets ER, and image tissue expressing ER receptors in vivo. Approximately 75% of newly diagnosed breast cancer has ER-positive expression [2]. Clinical studies have shown that 18F-FES PET can quantify ER expression in vivo and has the ability to predict the efficacy of ER-targeted or endocrine therapy.

2.3.1 18F-FES Uptake and Tumor ER Expression

Multiple studies have shown a correlation between FES uptake and ER expression by in vitro test in tumor lesions. Peterson et al. [66] reported, using SUV equal to 1.1 as a threshold to characterize ER-negative tumors and ER-positive tumors, the correlation between SUV and IHC index was 0.73. 18F-FES PET SUV is significantly associated with the size of primary breast tumors, and comparing with large breast tumors, 18F-FES PET has lower sensitivity [67]. Other factors may also affect FES uptake, such as premenopausal circulating estrogen levels, plasma sex hormone-binding globulin levels, and injected activity.

2.3.2 Ability of 18F-FES PET to Assess Heterogeneity of Disease

The main advantage of 18F-FES PET is its ability to evaluate the ER expression status of all tumor lesions simultaneously.

Traditionally, the state of ER expression in breast cancer is performed by quantitative or semiquantitative immunohistochemical staining on tissue specimens from local tissue biopsy and is easily limited by sampling error and tumor heterogeneity. Additionally, although primary breast tumors are positive for ER expression, its metastatic lesions may no longer express ER or express nonfunctional ER. Therefore, the results of local histological specimens cannot reliably represent the ER expression status of all lesions, but it is unrealistic to perform biopsy on all metastatic lesions.

In contrast, 18F-FES PET can assess ER expression over all tumor sites and provide a more comprehensive profile of the patient’s overall ER expression status. Clinical studies on 18F-FES PET have shown that 18F-FES uptake of all metastases sites (i.e., 18F-FES-positive and 18F-FES-negative lesions) are usually consistent with primary tumor in the same patient; there are a small number of patients demonstrated highly nonuniform 18F-FES uptake between primary tumor and metastases lesions and among different metastases lesions.

Potential differences in tumor ER status and 18F-FES uptake are particularly important in women with recurrent or metastatic disease.

2.3.3 Assess of Response to Endocrine Therapy

For ER-positive breast cancer patients, endocrine therapy achieves good results and has fewer side effects than traditional chemotherapy. Although ER-negative in vitro test suggests a lower likelihood of response and a poor prognosis, ER-positive does not ensure that it is effective to endocrine therapy.

Studies have shown that the efficacy of endocrine therapy is closely related to the FES uptake before treatment. The SUV of baseline 18F-FES PET can predict endocrine therapy response. Mortimer et al. [55] reported that the positive predictive value and negative predictive value were, respectively, 79%–87% and 88%–100%, when 2.0 was used as the threshold of SUV on baseline 18F-FES PET.

Both Linden et al. and Dehdashti et al. reported that 18F-FES PET for response assessment had a poor positive predictive value of 34%–50% [68, 69]. A recent study [70] by van Kruchten reported that the positive and negative predictive value of 18F-FES PET for response to therapy were 60% (95% CI: 31–83%) and 80% (95% CI: 38–96%), respectively, using SUVmax = 1.5 as a threshold.

Some studies supporting 18F-FES PET before therapy and early series of 18F-FDG PET to predict the response of endocrine therapy have cause debates about which method is more suitable for clinical use. Both tracers have high negative predictive value for endocrine therapy, but 18F-FDG PET has a higher positive predictive value.

The future workflow may be the combined of two methods. The first, the status of tumor ER expression is evaluated by 18F-FES PET, and then the response is evaluated by the series of FDG PET.

2.3.4 Application of 18F-FES PET in Non-breast Tumor

In addition to breast cancer, some diseases also have varying degrees of ER expression, such as endometrial cancer, epithelial ovarian cancer, and meningioma. In the future, 18F-FES PET could play an important role in confirming patients with epithelial ovarian cancer who would benefit from endocrine therapy for these.

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Copyright information

© Springer Nature Singapore Pte Ltd. and Shanghai Jiao Tong University Press 2019

Authors and Affiliations

  • Xinzhong Hao
    • 1
  • Xiaxia Meng
    • 1
  • Zhifang Wu
    • 1
  1. 1.The First Hospital of Shanxi Medical UniversityShanxiP. R. China

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