Coverage Policy Manual
Policy #: 2001036
Category: Radiology
Initiated: December 1999
Last Review: November 2021
  PET or PET/CT for Breast Cancer

Description:
Note:  This policy is intended for those members with contracts that do not have requirements for prior approval for imaging procedures through an independent imaging review organization.
 
 
Positron Emission Tomography (PET) imaging uses radiotracers that can reveal both anatomical and physiological information.  The glucose analog, 2-[fluorine-18]-Fluoro-2-deoxy-D-glucose (FDG) is useful in cancer imaging because it has been found that tumor cells show increased utilization of glucose compared to non-malignant tissue and is the most common radiotracer that is utilized. For certain malignancies PET scans have been shown to be more accurate than other non-invasive tests in detecting malignant disease.  However, as with all diagnostic tests, PET scans do not detect cancer 100% of the time that cancer is present (a false negative test), nor do all positive PET scans represent the presence of malignant disease (a false positive test).  A false negative test may occur because a critical volume of malignant cells is necessary for a PET scan to be positive. PET scans may be false positive in the presence of inflammation or granulomatous disease.
 
There is no data on PET scanning for selecting which patient with a low suspicion mammogram should have a biopsy.
 
The sensitivity and specificity of PET scanning for staging axillary nodes are 80% and 89%, respectively.  These values are too low to recommend use of PET for determining which patient should have axillary dissection or which patient should have radiation therapy or chemotherapy.
 
The sensitivity and specificity of PET scanning for staging prior to initial therapy have varied considerably in reported studies which prevents determination of whether this use of PET scanning is effective.
 
Few studies have reported on use of PET to detect recurrence of metastases in sites other than bone.  One study did not report histologic comparison, and the only other study did not demonstrate that PET was as effective as radionuclide bone scanning.  Because of limited sensitivity and specificity, it is difficult to determine from studies on PET for detection of recurrence in other organs whether the test changes therapy.
 
PET, using an estrogen labeled radiotracer to identify estrogen receptor status, was positive in only 89% of patients compared to histological biopsy results.
 
Definitions
 
Screening – testing in the absence of an established or clinically suspected diagnosis
 
Diagnosis - testing based on a reasonable clinical suspicion of a particular condition or disorder
 
Diagnostic Workup – initial staging of documented malignancy
 
Management – testing to direct therapy of an established condition, which may include preoperative or postoperative imaging, or imaging performed to evaluate the response to nonsurgical intervention. In oncologic imaging, management applies to patients with measurable disease and to imaging performed before or after planned treatment intervention, therapy response, restaging or clinically suspected recurrence.
 
Surveillance – periodic assessment following completion of therapy. In oncologic imaging, surveillance applies to asymptomatic patients in remission and/or without measurable disease
 
Cannot be performed or is nondiagnostic – applies when the test:
    • Is positive or indeterminate for clinically significant pathology when the information provided about the abnormality by the test is not sufficient to direct subsequent management
    • Is negative when the negative likelihood ratio of the test is both insufficient to confidently exclude the absence of suspected disease and unable to direct subsequent management. This typically applies in scenarios with moderate to high clinical pretest probability with negative testing or low pretest probability with clear evidence for net benefit
    • Has been previously nondiagnostic because of a persistent clinical factor (e.g., body habitus, immobility) that is very likely to make retesting nondiagnostic as well Cannot be performed due to a medical contraindication (e.g., contrast nephrotoxicity, allergy, or in highly radiation sensitive populations such as pediatrics and pregnancy) or reasonable unavailability related to lack of local expertise or service availability
Standard or conventional imaging: Refers to imaging that does not require a PET/CT. Depending on the clinical scenario and individual patient circumstances, this may include computed tomography, magnetic resonance imaging, ultrasound and/or scintigraphy.
 
 

Policy/
Coverage:
Effective March 13, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
FDG-PET/CT for patients with Breast Cancer meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes and is covered for:  
Diagnostic Workup:
Indicated in EITHER of the following:
        • Locally advanced disease (stage IIIA-IIIC) has been established and standard imaging cannot be performed or is nondiagnostic for metastatic disease; or
        • Clinical suspicion for metastatic disease when standard imaging cannot be performed or is non diagnostic for metastatic disease
 
Management:
Indicated in ANY of the following:
        • Standard imaging cannot be performed or is nondiagnostic for recurrent or progressive disease; or
        • Evaluation of elevated LFTs or rising tumor markers when standard imaging has not clearly identified a site of recurrence or progression; or
        • Restaging/treatment response when bone is the only site of measurable disease in the chest, abdomen, and pelvis
 
For fully-insured contracts subject to Act 583 of Arkansas legislature, please see ABCBS policy 2021004, Surveillance and Other PET Oncologic Applications.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
PET/CT for patients with Breast Cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or any circumstance other than those listed above including but not limited to:
    • Suspected breast cancer
    • Surveillance*
    • 18F-FES-PET/CT scanning
 
For members with contracts without primary coverage criteria, PET/CT for patients with Breast Cancer is considered investigational for any indication or any circumstance other than those listed above including but not limited to:
    • Suspected breast cancer
    • Surveillance *
    • 18F-FES-PET/CT scanning
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
*For fully-insured contracts subject to Act 583 of Arkansas legislature, please see ABCBS policy 2021004, Surveillance and Other PET Oncologic Applications.
 
Note: Standard or conventional imaging: Refers to imaging that does not require a PET/CT. Depending on the clinical scenario and individual patient circumstances, this may include computed tomography, magnetic resonance imaging, ultrasound and/or scintigraphy.
 
 
Effective Prior to March 13, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
FDG-PET/CT for patients with Breast Cancer meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for:
 
Diagnostic Workup
 
Indicated in EITHER of the following:
      • Locally advanced disease (stage IIIA-IIIC) has been established and standard imaging cannot be performed or is nondiagnostic for metastatic disease; or
      • Clinical suspicion for metastatic disease when standard imaging cannot be performed or is non diagnostic for metastatic disease.
 
Treatment Management
 
Indicated in ANY of the following:
      • Standard imaging cannot be performed or is nondiagnostic for recurrent or progressive disease; or
      • Clinical suspicion for worsening of disease when standard imaging has not clearly identified a site of recurrence or progression; or
      • Restaging/treatment response when bone is the only site of measurable disease in the chest, abdomen, and pelvis.  
 
For fully-insured contracts subject to Act 583 of Arkansas legislature, please see ABCBS policy 2021004, Surveillance and Other PET Oncologic Applications.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
PET/CT for patients with Breast Cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:  
        • For screening and surveillance*; or
        • For any other indication not specifically listed above.
 
*For fully-insured contracts subject to Act 583 of Arkansas legislature, please see ABCBS policy 2021004, Surveillance and Other PET Oncologic Applications.
 
For members with contracts without primary coverage criteria, PET/CT for patients with Breast Cancer is considered investigational:  
        • For screening and surveillance; or
        • For any other indication not specifically listed above.  
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Effective Prior to August 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
FDG-PET/CT for patients with Breast Cancer meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for:
 
Diagnostic Workup
 
Indicated in EITHER of the following:
 
      • Locally advanced disease (stage IIIA-IIIC) has been established and standard imaging cannot be performed or is nondiagnostic for metastatic disease; or
      • Clinical suspicion for metastatic disease when standard imaging cannot be performed or is non diagnostic for metastatic disease.
 
Treatment Management
 
Indicated in ANY of the following:
 
      • Standard imaging cannot be performed or is nondiagnostic for recurrent or progressive disease; or
      • Clinical suspicion for worsening of disease when standard imaging has not clearly identified a site of recurrence or progression; or
      • Restaging/treatment response when bone is the only site of measurable disease in the chest, abdomen, and pelvis.  
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
PET/CT for patients with Breast Cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:
 
    • For screening and surveillance; or
    • For any other indication not specifically listed above.
 
 
For members with contracts without primary coverage criteria, PET/CT for patients with Breast Cancer is considered investigational:
 
    • For screening and surveillance; or
    • For any other indication not specifically listed above.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective March 2018 to June 15, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
“PET scan” refers to FDG PET or PET/CT.
 
Positron emission tomography scanning meets primary coverage criteria for effectiveness and is covered:
 
    • As an adjunct to other imaging modalities for staging and restaging of locoregional recurrence or metastasis;  
    • To monitor chemotherapy when done after the first or second cycle of chemotherapy to determine the effect of chemotherapy on the tumor. If PET shows no tumor response to therapy and a different chemotherapy regimen is initiated, PET may be repeated in 4-6 weeks to determine chemotherapy effectiveness.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
PET scan for surveillance of women who have been treated for breast cancer and have no symptoms, signs, or other indication of recurrence of the cancer does not meet member certificate of coverage Primary Coverage Criteria for effectiveness.
 
For members with contracts without primary coverage criteria, PET scan for surveillance of women who have been treated for breast cancer and have no symptoms, signs, or other indication of recurrence of the cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
PET scanning to establish a diagnosis of breast cancer, does not meet member certificate of coverage Primary Coverage Criteria for effectiveness.
 
For members with contracts without primary coverage criteria, PET scanning to establish a diagnosis of breast cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
PET scan for staging of axillary lymph nodes does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, PET scan for staging of axillary lymph nodes is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
PET scanning to predict pathologic response to neoadjuvant therapy for locally advanced disease, does not meet member certificate of coverage Primary Coverage Criteria for effectiveness.
 
For members with contracts without primary coverage criteria, PET scanning to predict pathologic response to neoadjuvant therapy for locally advanced disease is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
PET scanning for initial staging or restaging of tumors that are known not to be 18FDG-avid does not meet member certificate of coverage Primary Coverage Criteria for effectiveness.
 
For members with contracts without primary coverage criteria, PET scanning for initial staging or restaging of tumors that are known not to be 18FDG-avid is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
The use of PET scanning for patients with breast cancer for any reason other than those specifically addressed above is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For those contracts without Primary Coverage Criteria the use of PET scanning for patients with breast cancer for any reason other than those specifically addressed above is considered investigational and is not covered. Investigational services are an exclusion in the member certificate of coverage.
 
Effective Prior to March 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
“PET scan” refers to FDG PET or PET/CT.
 
Positron emission tomography scanning meets primary coverage criteria for effectiveness and is covered:
    • As an adjunct to other imaging modalities for staging and restaging of locoregional recurrence or metastasis;  
    • To monitor chemotherapy when done after the first or second cycle of chemotherapy to determine the effect of chemotherapy on the tumor. If PET shows no tumor response to therapy and a different chemotherapy regimen is initiated, PET may be repeated in 4-6 weeks to determine chemotherapy effectiveness.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
PET scan for surveillance of women who have been treated for breast cancer and have no symptoms, signs, or other indication of recurrence of the cancer does not meet member certificate of coverage Primary Coverage Criteria for effectiveness. (Podoloff, et al, JNCCN, 2009; 7 Suppl 2:S1-S23)
 
PET scanning should not be used to establish a diagnosis of breast cancer.
 
PET scanning should not be done for initial staging or restaging of tumors that are known not to be 18FDG-avid. (Juweid ME, Cheson BD. NEJM, 2006;354:496-507)
 
The use of PET scanning for patients with breast cancer for any reason other than those specifically addressed above is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For those contracts without Primary Coverage Criteria the use of PET scanning for patients with breast cancer for any reason other than those specifically addressed above is considered investigational and is not covered. Investigational services are an exclusion in the member certificate of coverage.

Rationale:
An article by Juweid and Cheson reviews the use of PET to monitor tumor response and to assess tumors after therapy.  The only current clinical indication for monitoring response to chemotherapy is in breast cancer and the reference articles refer to the primary treatment of breast cancer.  Periodic PET scanning in patients without clinical or biochemical evidence of disease should be avoided.
 
2013 Update:
A review of literature on PubMed through January 2013 was performed. There were no published articles identified that would prompt a change in the coverage statement.
 
Zucchini and colleagues (2013) published the results of a study done to assess the potential clinical utility of (18)F-FDG-PET/CT to allow early treatment changes during preoperative chemotherapy in patients with early/locally advanced breast cancer. Sixty patients who were newly diagnosed with early/locally advanced breast cancer were included in the study.  Each had received 6-8cycles of preoperative chemotherapy. Optimal pathologic response was the absence of cancer cells in breast and axillary lymph nodes. All other conditions were defined as pathologic non-response.  PET/CT was done at baseline and after 2 cycles of chemotherapy.  Metabolic response was defined as maximum standardized uptake value percentage changes  >50% and was compared with pathologic response rates.  Thirteen (22%) patients achieved pathologic response.  According to immunohistochemistry, 16% of ER-positive/HER2-negative patients, 29% of HER2-positive and 27% triple negative patients achieved pathologic response.  PET/CT showed the highest specificity (38%) and negative predictive value (100%) in ER-positive/HER2-negative patients.  Early metabolic non-response was always associated to pathologic non-response and poor prognosis in ER-positive/HER2-negative patients. In this subgroup, FDG PET/CT might be useful to select patients who will probably benefit from early therapeutic strategy modifications.
 
Choi and colleagues (2012) investigated the potential effects of (18)F-FDG PET/CT in the initial assessment of patients with primary breast cancer.  From January 2008 to December 2009, 154 consecutive biopsy-proven invasive breast cancer patients were enrolled in this study. Patients underwent conventional imaging studies including mammography, breast ultrasonography (USG), and MRI for local assessment, and chest X-ray, liver USG, and bone scan to rule out distant metastasis. All 154 patients underwent (18)F-FDG PET/CT in the initial assessment.   FDG PET/CT did not detect primary breast lesions in 16 patients with a sensitivity of 89.6% and detected only 5 multiple lesions (12.5%) out of 40 cases. Histologically confirmed axillary lymph node (LN) metastases were in 51 patients, and the sensitivity and specificity of (18)F-FDG PET/CT to detect metastatic axilla were 37.3% and 95.8%, respectively; whereas the corresponding estimates of USG were 41.2% and 93.7%, respectively.  Eleven extra-axillary LN metastases were found in eight patients, and seven lesions were detected by (18)F-FDG PET/CT only. The sensitivity and specificity of (18)F-FDG PET/CT in detecting distant metastasis were 100% and 96.4%, respectively; whereas the sensitivity and specificity of the conventional imaging were 61.5% and 99.2%, respectively.  The authors concluded that  FDG PET/CT cannot be recommended as a primary diagnostic procedure in breast cancer, but it has the potential to be used as an additional imaging tool for the detection of axillary metastasis, distant metastasis, and extra-axillary LN metastasis.
 
Hatt and colleagues (2013) published the results of a study done  to determine the best predictive factor among image-derived parameters extracted from sequential (18)F-FDG PET scans for early tumor response prediction after 2 cycles of neoadjuvant chemotherapy in breast cancer.  Fifty-one  breast cancer patients were included.  Responder and nonresponder status was determined by histopathologic examination according to the tumor and node Sataloff scale.  PET indices (maximum and mean standardized uptake value [SUV], metabolically active tumor volume, and total lesion glycolysis [TLG]), at baseline and their variation  after 2 cycles of neoadjuvant chemotherapy were extracted from the PET images. Their predictive value was investigated using Mann-Whitney U tests and receiver-operating-characteristic analysis. Subgroup analysis was also performed by considering estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, triple-negative, and HER2-positive tumors separately. The impact of partial-volume correction was also investigated using an iterative deconvolution algorithm.   There were 24 pathologic nonresponders and 27 responders. None of the baseline PET parameters was correlated with response. After 2 neoadjuvant chemotherapy cycles, the reduction of each parameter was significantly associated with response, the best prediction of response being obtained with TLG variation (96% sensitivity, 92% specificity, and 94% accuracy), which had a significantly higher area under the curve (0.91 vs. 0.82, P = 0.01) than did SUV(max) variation (63% sensitivity, 92% specificity, and 77% accuracy).  Subgroup analysis confirmed a significantly higher accuracy for  TLG variation than SUV variation for ER-positive/HER-negative but not for triple-negative and HER2-positive tumors. Partial-volume correction had no impact on the predictive value of any of the PET image-derived parameters despite significant changes in their absolute values.
 
The authors concluded that the reduction after 2 neoadjuvant chemotherapy cycles of the metabolically active volume of primary tumor measurements such as TLG variation predicts histopathologic tumor response with higher accuracy than does SUV variation measurements, especially for ER-positive/HER2-negative breast cancer. These results should be confirmed in a larger group of patients as they may potentially increase the clinical value and efficiency of  FDG PET for early prediction of response to neoadjuvant chemotherapy.
 
 
NCCN Guidelines on Breast Cancer Version 3.2012:
    • NCCN Panel recommends against the use of PET or PET/CT in the staging of patients with  stage I-IIB disease.
    • For patients with stage IIIA (category 2B) disease, FDG PET is optional.
    • For patients with Stage III invasive disease, the consensus of the Panel is that FDG PET/CT is most helpful when standard imaging results are equivocal or suspicious and to detect regional node involvement as well as distant metastases.
    • PET scans in the asymptomatic patient provide no advantage in survival or ability to palliate recurrent disease and are not recommended.
 
ACR Appropriateness Criteria:
American College of Radiology Appropriateness Guidelines (June 2012) for FDG PET/CT imaging:
   (Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate)
 
    • Rule out metastasis – Stage I breast carcinoma in asymptomatic woman
        • Appropriateness rating: 2
 
2014 Update
 
A literature search conducted through October 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A 2013 meta-analysis by Hong et al reported sensitivity and specificity of PET-CT in diagnosing distant metastases in breast cancer patients were 0.96 (95% confidence interval [CI], 0.90 to 0.98) and 0.95 (95% CI, 0.92 to 0.97) when 8 studies totaling 748 patients were evaluated (Hong, 2013). When the meta-analysis was completed on 6 comparative studies totaling 664 patients, the sensitivity and specificity were 0.97 (95% CI, 0.84 to 0.99) and 0.95 (95% CI, 0.93 to 0.97), compared with 0.56 (95% CI, 0.38 to 0.74) and 0.91(95% CI, 0.78 to 0.97) with conventional imaging.
 
Rong et al in 2013 meta-analyzed 7 studies totaling 668 patients and reported PET-CT sensitivity and specificity were greater than bone scintigraphy for detecting bone metastasis in breast cancer patients (Rong, 2013). PET-CT sensitivity and specificity were 0.93 (95% CI, 0.82 to 0.98) and 0.99 (95% CI, 0.95 to 1.00), compared with 0.81 (95% CI, 0.58 to 0.93) and 0.96 (95% CI, 0.76 to 1.00) with bone scintigraphy.
 
2015 Update
 
A literature search conducted through January 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In a meta-analysis of 8 studies (total N=873) of FDG-PET in women with suspicious breast lesions, Caldarella and colleagues reported pooled sensitivity and specificity of 0.85 (95% CI, 0.83 to 0.88) and 0.79 (95% CI, 0.74 to 0.83), respectively, on a per-lesion-basis (Caldarella, 2014). As previously noted, a false-negative rate of 15% (1-sensitivity) may be considered unacceptable given the relative ease of breast biopsy.
 
A 2007 NCCN review of PET concluded that PET is optional and may be useful for staging and restaging regional or distant metastasis when suspicion is high and other imaging is inconclusive.20 Current NCCN guidelines include an optional category 2B recommendation for FDG-PET/CT in the work-up of clinical stage IIIA breast cancer (NCCN, 2014). NCCN recommends against FDG-PET/CT for lower stage breast cancer due to high false-negative rates in detecting low-grade lesions or lesions less than 1 cm; low sensitivity in detecting axillary node metastasis; low prior probability of detectable metastases in these patients; and high-false positive rates. PET or PET/CT is considered most helpful when “standard staging studies are equivocal or suspicious, especially in the setting of locally advanced or metastatic disease.” Additionally, NCCN guidelines do not recommend routine use of PET scans in asymptomatic patients for surveillance and follow-up after breast cancer treatment.
 
2018 Update
 
Annual policy review completed with a literature search using the MEDLINE database through February 2018. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Breast Cancer Restaging
A 2016 systematic review by Xiao et al evaluated the diagnostic efficacy of 18F-FDG-PET and 18F-FDGPET/CT in detecting breast cancer recurrence (Xiao, 2016). The literature search, conducted through January 2016, identified 26 studies (total N=1752 patients) for inclusion in the analysis; 12 studies used PET and 14 studies used PET/CT. Fourteen studies had QUADAS scores greater than 10. Reasons for suspected recurrence in the 1752 patients were: elevated tumor markers (57%), suspicion from conventional imaging modalities (34%), and suggestive clinical symptoms or physical examination results (9%). Pooled sensitivity and specificity for PET and PET/CT were 90% (95% CI, 88% to 90%) and 81% (95% CI, 78% to 84%), respectively. Subgroup analyses showed that PET/CT was more specific than PET alone in diagnosing recurrent breast cancer (p=0.035).
 
A systematic review by Liu et al compared 18F-FDG-PET or PET/CT with MRI in assessing pathologic complete response to neoadjuvant chemotherapy in patients with breast cancer (Liu, 2016). The literature search, conducted through August 2015, identified 6 studies (total N=382 patients) for inclusion. Quality assessment of the studies was satisfactory using the QUADAS-2 scale. Meta-analysis showed that 18F-FDG-PET or -PET/CT was more sensitive than MRI and MRI was more specific than 18F-FDGPET or -PET/CT in assessing complete response to neoadjuvant chemotherapy. The pooled sensitivities and specificities for 18F-FDG-PET or -PET/CT were 86% (95% CI, 76% to 93%) and 72% (95% CI, 49% to 87%) and 65% (95% CI, 45% to 80%) and 88% (95% CI, 75% to 95%), for MRI, all respectively.
 
In another meta-analysis comparing 18F-FDG-PET with MRI and evaluating pathologic complete response to neoadjuvant chemotherapy (NAC) in patients with breast cancer, Sheikhbahaei et al selected 10 studies for analysis (Sheikhbahaei, 2016).  
 
Evidence for the use of PET or PET/CT in patients with breast cancer consists of TEC Assessments, systematic reviews, and meta-analyses. There is no evidence that PET is useful in diagnosing breast cancer. The false-negative rates of PET in patients with breast cancer are estimated to be between 5.5% and 8.5%, which can be considered unacceptable, given that breast biopsy can provide more definitive results. PET/CT might be useful in detecting metastases when results from other imaging techniques are inconclusive. The evidence supports the use of 18F-FDG-PET and 18F-PET/CT for staging and restaging only if standard staging methods are inconclusive, but does not support their use for diagnosis, staging/restaging when standard staging methods are conclusive, and or surveillance.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2019. No new literature was identified that would prompt a change in the coverage statement.  
 
2020 Update
A literature search was conducted through January 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2021. No new literature was identified that would prompt a change in the coverage statement.
 
November 2021 Update
A literature review was performed through September 2021. Following is a summary of the key literature to date.
 
SUSPECTED CANCER
Imaging cannot replace tissue diagnosis, and suspicious lesions should be biopsied. MRI breast may be indicated in high-risk patients without a positive biopsy. MRI breast has been shown to have improved sensitivity over conventional mammographic imaging; however, limited data exists to support the use of MRI in patients with a lumpy, dense, clinically negative breast exam and normal conventional imaging. Although the risk of malignancy with a mammogram designated as BI-RADS3 is relatively low (0.3%-2%), some experts recommend follow-up with MRI in this scenario. MRI can also assess possible mammographically-occult primary breast cancer when presenting with supraclavicular or axillary nodal metastases. (2)
 
DIAGNOSTIC WORKUP
Breast cancer is staged using the American Joint Committee on Cancer TNM system. Advanced imaging should be guided by stage and other presenting symptoms. In a large single-institution retrospective study of newly diagnosed asymptomatic breast cancer, bone scan detected bony metastases in 6% of patients (stage I 5%, stage II 6%, and stage III 14%), liver ultrasound detected hepatic metastases in 0.7% of patients (stage I or II 0%, and stage III 6%), and chest X-ray detected lung metastases in 0.9% of patients (stage I or II 0% and stage III 7%). However, there was an unacceptably high rate of false positives: 6% for bone scans, 6% for liver ultrasounds, and 3% for chest X-rays.(3) Ravaioli et al. reported the rate of metastases detection in asymptomatic breast cancer patients was 1.46% for stage I and II versus 10.68% for stage III.(4) A review of 20 studies similarly showed that bone scan detected skeletal metastases in 0.5%-6.8% of those with stage I, 2.4%-8.8% with stage II, and 8.3%-24.5% with stage III breast cancer. The detection of liver and bone metastases ranged from 0%-1.7% in stage I-II patients and 1.7%-2% for stage III patients. Falsepositive rates were 10%-22% for bone scan, 33%-66% for liver ultrasonography, and 0%-23% for chest radiography. (5) Based on the poor sensitivity and specificity of imaging in asymptomatic early stage breast cancer, imaging should be reserved for evaluation of specific signs or symptoms suggestive of metastatic disease.
 
The use of PET or PET/CT is not indicated in the routine staging of clinical stage I, stage II or operable stage III (T3 N1) breast cancer, supported by studies detailing the high false-negative rate in the detection of lesions that are small (<1 cm), low sensitivity for detecting axillary nodal metastases, low probability of these patients having detectable metastatic disease, and high rate of false-positive scans. (6-9) In the setting of metastatic disease found on conventional imaging, there is insufficient data and limited evidence to show PET scan alters treatment. In a prospective study (N=178) by Jeong et al, patients without clinically detected axillary node metastases had virtually no benefit from PET/CT scan; management was changed in only 1.7% of patients. (10) However, for locally advanced disease, a higher proportion (7%-13%) had changes in management based on PET/CT imaging. (11) The National Comprehensive Cancer Network (NCCN) has designated PET/CT scan as optional, most helpful in situations where standard staging studies are equivocal or suspicious, especially in the setting of locally advanced or metastatic disease. (12) The utility of preoperative MRI breast is controversial and is not universally recommended. In 2 prospective trials, the rate of postoperative re-excision was unaffected by preoperative MRI. (13, 14) In a meta-analysis of 4 studies by Houssami et al, (N=3169 patients), there was no difference in the rate of local recurrence or disease-free survival at 8 years for patients receiving a preoperative breast MRI compared with those without preoperative imaging.15 The NCCN designates MRI breast as an optional imaging test. (12)
 
MANAGEMENT
Response to therapy based on PET/CT imaging has been correlated with longer time to progression but whether this translates into improved patient outcomes is unknown.16 In a comparative study of 17 single-institution, nonrandomized, observational studies, PET/CT response correlated with changes in tumor volume as determined by bone scan, MRI, and/or CT; however, performance compared to conventional modalities and overall clinical impact could not be determined.17 PET imaging is designated as optional by the NCCN. (12) In the unique scenario of bone-only metastases, the AIM External Expert Advisory Board allows for disease monitoring with PET imaging, as restaging with CT or MRI is expected to result in suboptimal distinction between treated and residual/recurrent bone disease.
 
The FDA has approved 18F-fluoroestradiol (18F-FES) for use as an adjunct to biopsy in metastatic or recurrent breast cancer. (18) There is a high correlation between 18F-FES uptake and estrogen receptor (ER) expression on immunohistochemistry. (19) However, decisions regarding therapy rely on both ER status as well as HER2 status. The current standard of care, immunohistochemistry, allows evaluation of ER, PR, and HER2 status. Because 18F-FES does not evaluate HER2 status, there is no evidence that it provides sufficient information to direct management.
 
SURVEILLANCE
Both the American Society of Clinical Oncology and the NCCN discourage the use of advanced body imaging for surveillance of treated, asymptomatic breast cancer.(12, 20) Early detection has not been shown to provide an advantage in survival or the ability to palliate recurrent disease and there is no evidence to support the use of CT, MRI, or PET scan.(7) The NCCN recommends annual mammography surveillance for patients who have had breast conserving surgery and radiation therapy, but does not recommend routine imaging following breast reconstruction.(12) The American College of Radiology (ACR) Appropriateness Criteria considers MRI and other advanced imaging modalities usually inappropriate for the mastectomy or reconstruction side(s) in patients with a history of breast cancer. (2) Breast MRI may be considered in women treated with breast conserving therapy with high lifetime risk (greater than 20% based on models largely dependent on family history) of developing a second primary breast cancer. Increased rates of contralateral breast cancer are reported in women with BRCA1/2 mutations, when compared with to patients with sporadic breast cancer.(22-24)
 
Current References
    1. Li CI, Uribe DJ, Daling JR. Clinical characteristics of different histologic types of breast cancer. Br J Cancer. 2005;93(9):1046-52. PMID: 16175185
    2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Occult Primary (Cancer of Unknown Primary [CUP]) (Version 2.2021). Available at http://www.nccn.org. ©National Comprehensive Cancer Network, 2021.
    3. Puglisi F, Follador A, Minisini AM, et al. Baseline staging tests after a new diagnosis of breast cancer: further evidence of their limited indications. Ann Oncol. 2005;16(2):263-6. PMID: 15668281
    4. Ravaioli A, Pasini G, Polselli A, et al. Staging of breast cancer: new recommended standard procedure. Breast Cancer Res Treat. 2002;72(1):53-60. PMID: 12000220
    5. Myers RE, Johnston M, Pritchard K, et al. Baseline staging tests in primary breast cancer: a practice guideline. CMAJ. 2001;164(10):1439-44. PMID: 11387916
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    18. U.S. Food & Drug Administration (FDA). CERIANNA™ (fluoroestradiol F 18) Injection, for intravenous use. (2020 [revised 05/2020]). Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212155s000lbl.pdf.
    19. Evangelista L, Guarneri V, Conte PF. 18F-fluoroestradiol positron emission tomography in breast cancer patients: systematic review of the literature & meta-analysis. Curr Radiopharm. 2016;9(3):244-57. PMID: 27774910
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CPT/HCPCS:
78811Positron emission tomography (PET) imaging; limited area (eg, chest, head/neck)
78812Positron emission tomography (PET) imaging; skull base to mid thigh
78813Positron emission tomography (PET) imaging; whole body
78814Positron emission tomography (PET) with concurrently acquired computed tomography (CT) for attenuation correction and anatomical localization imaging; limited area (eg, chest, head/neck)
78815Positron emission tomography (PET) with concurrently acquired computed tomography (CT) for attenuation correction and anatomical localization imaging; skull base to mid thigh
78816Positron emission tomography (PET) with concurrently acquired computed tomography (CT) for attenuation correction and anatomical localization imaging; whole body
A9591Fluoroestradiol f 18, diagnostic, 1 millicurie

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