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Blue Cross and Blue Shield of Montana (BCBSMT) considers evaluation of biomarker genes experimental, investigational and unproven for detection of lymph node metastases in patients with breast cancer.
There are no specific procedure codes identifying this technology. It is likely a variety of procedure codes may be used, including but not limited to 88387 and 88388.
A 2007 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment evaluated the intraoperative use of the GeneSearch™ breast lymph node assay in detecting early-stage breast cancer metastases in the sentinel lymph nodes compared to 1) postoperative histology, or 2) other commonly used intraoperative evaluation methods, namely, intraoperative frozen section histology or imprint cytology. (2)
Published studies provided evidence on the performance of the GeneSearch assay (1, 2, 3); additional information includes the manufacturer’s submissions to the (U.S. Food and Drug Administration (FDA) and other materials from the meeting of the Immunological Devices Panel meeting on November 16, 2006. (4, 5, 6) The published study reports on 416 subjects from 11 sites in the U. S. Patients were diagnosed with breast cancer and were 18 years or older and were scheduled for sentinel lymph node biopsies (SLNB). The GeneSearch assay was performed alongside other tests commonly used at each facility; the GeneSearch results were not used for clinical management. The assay was compared to a reference standard, postoperative histology (primary study outcome), and to other intraoperative techniques that were routinely conducted by the participating institution, namely, frozen section histology and imprint cytology. Among the 416 patients with postoperative histology results, 29.1% had positive lymph nodes for metastases, with a range across sites of 14.3% to 45.5%.
Compared to the reference standard, the sensitivity of the GeneSearch assay was 87.6% (95% CI [confidence interval]: 80.4%–92.9%); the specificity was 94.2% (95% CI: 90.9%–96.6%); the positive predictive value was 86.2% (78.8%–91.7%); and the negative predictive value was 94.9% (91.7%–97.1%). The sensitivity was higher (97.9%; 95% CI: 92.5%–99.7%) for patients with macrometastases than for those with micrometastases (56.5%; 95% CI: 34.5%–76.8%). The authors assert that the false-positive rate may be lower than reported, because the results may be based on examination of parts of the lymph node that contain metastases, while the postoperative histology slides may come from a different slice of the node without metastases, i.e., differences may be due to sampling distinct parts of the lymph node. While the researchers provide suggestive evidence, further research is needed to confirm or deny this hypothesis.
The other published study (3) included data from a beta trial to determine threshold levels of mammaglobin and cytokeratin-19 correlating with metastases larger than 0.2mm.
The study presented to the FDA has a number of strengths, including the clear distinction between the training and test sets and double-reading of the permanent histology slides to increase the reliability of the reference standard. However, a number of weaknesses are present as well, such as lack of description regarding patient recruitment; substantial variation in assay performance across sites; lack of corroborating studies; inability of the assay to distinguish between micro- and macrometastases; and a learning curve for those performing the assay.
The key factor in assessing this assay is the tradeoff between avoiding a second surgery to remove axillary lymph nodes if the sentinel node is positive versus risking unnecessary axial lymph node dissections (ALNDs) if the assay produces a false positive result. The reason SLNB is the standard of care in early breast cancer, in spite of the fact that trials on its impact are still incomplete, is the desire to avoid ALND when possible, given the potential for significant, long-term morbidity. While the researchers conducting the GeneSearch study suggest that many of the false-positive assay results detect real metastases in the additional sections of the node used for the assay, the evidence presented to support this argument is insufficient. Given that GeneSearch was not used for patient treatment decisions in this study, longer term follow-up of patients with false-positive test results to see if and when axillary metastases develop might be informative, although the utility of this approach may be compromised by the small number of patients involved.
As for avoiding a second surgery and undergoing an unnecessary ALND, patient preferences should play an important role in this decision. The FDA is requiring informed consent for participants in one of the postmarketing studies. Although the number of unnecessary ALNDs is substantially smaller than the number of second surgeries avoided, the “harms” from the former are more common and generally longer lasting than those associated with needing a second surgery. The sequelae of ALND can last for years or even a lifetime. The inconvenience of a second surgery, while difficult for patients coping with a serious diagnosis and substantial course of treatment, is likely to be short lived. For these women, the harms of ALND are unavoidable.
As for how the sensitivity and specificity of intraoperative use of GeneSearch during sentinel lymph node biopsy compare to those of alternative intraoperative tests (i.e., imprint cytology and frozen section histology), the test set data provided to the FDA are useful, as they provide a direct comparison of the tests in the same patients. Several concerns, however, are outlined below.
- The comparison of GeneSearch to alternative, intraoperative tests was not planned; not all study sites performed such tests.
- The sample size of 29 for the imprint cytology comparison is too small to be meaningful.
- The alternative tests were not conducted with the rigorous double-reading, review by central laboratory pathologists, and reconciliation of discrepancies applied to the reference standard.
- The statistical approach to evaluating the difference in the test characteristics between GeneSearch and frozen section histology is not well described.
The focus here is on which technique—the assay, frozen section histology, or imprint cytology—performs best at avoiding second surgeries versus undergoing unnecessary ALNDs. The data on imprint cytology are inadequate and will not be discussed further. Also, evidence is inadequate to determine whether the GeneSearch assay outperforms frozen section histology. However, a receiver operating characteristic (ROC) analysis conducted by the FDA suggests that the GeneSearch assay and frozen section histology operate at different points on the same or very similar ROC curves. If this is correct (the analysis is not sufficiently detailed to assess this), then the question is not whether one technique is better than the other overall, but what the optimal tradeoff (and therefore assay cutoff) is between false-positive and false-negative results. Increasing the sensitivity of the test while sacrificing some specificity, as the GeneSearch assay does, may not be optimal, given the longer term and potentially more serious sequelae from ALND than from a second surgery.
The GeneSearch assay also provides less information for staging than other intraoperative procedures, since it cannot distinguish between micro- and macrometastases. Nor can it indicate the location of the metastasis (inside or outside of the node). Postoperative histology is, therefore, required in all cases. It is less crucial when frozen section histology is performed, since pathologists can judge the size of the metastasis and its location from this test, although distortion is possible.
In summary, the data available are inadequate to assess the clinical utility and the impact on health outcomes of the GeneSearch assay compared to either postoperative histology alone or to alternative intraoperative tests such as imprint cytology and frozen section histology. In addition, the balance of benefits versus harms may require higher specificity to avoid unnecessary ALNDs and their sequelae, whereas the GeneSearch design emphasizes sensitivity. Patient preferences should also play a key role in this calculation.
Therefore, based on the above concerns regarding the single, published study for GeneSearch, its use at this time is considered experimental, investigational and unproven.
Several published reports from European centers describe the use of similar tests. (7, 8) Berger and colleagues reported on sensitivity and specificity of cytokeratin-19, mammaglobin, and DNA methyltransferase 3b (alone and in combination) in the evaluation of 290 axillary lymph nodes from 29 patients with breast cancer. (9) Compared to standard histology, sensitivity of the individual markers varied with mammaglobin at 68% and cytokeratin-19 at 96%. Dell’Orto reported on results from qualitative and quantitative assays of mammaglobin1 mRNA in evaluating sentinel lymph nodes. (10) In the validation sample, the quantitative assay had a sensitivity of 75% and specificity of 95% compared to standard histopathology.
At the present time, given the lack of FDA approval for these other assays, and the limited published information about these tests, their use is considered experimental, investigational and unproven.
A search of peer reviewed literature through February 2011 identified clinical trial information. The following is a summary of the key literature to date.
Martin-Martinez et al. published the results of a prospective study validating the use of the GeneSearch assay at their institution to detect the presence of metastases larger than 0.2 mm. (11) The study included 123 sentinel lymph nodes from 78 patients who underwent surgical lumpectomy and sentinel lymph node biopsy. Sentinel lymph nodes were analyzed by the GeneSearch assay and postoperative histology (hematoxylin and eosin stain [H&E] and immunohistochemistry [IHC]). The pathologist examining the postoperative H&E and IHC was blinded to the assay results. Thirteen cases were considered sentinel lymph node positive (metastasis larger than 0.2 mm) based on histology and 14 based on the assay. Of the 14 assay-positive cases, two were negative when assessed histologically. Conversely, one case that was negative by the assay, showed a micrometastatic focus (0.25 mm) with IHC. The assay results corroborated with the histologic results in 75 of 78 patients for an overall agreement of 96%, sensitivity of 92%, and specificity of 97%. Positive and negative predictive values of the assay were 86% and 98%, respectively. No patient management decisions were made based on the GeneSearch assay results.
Viale et al. prospectively assessed the accuracy of the GeneSearch assay by evaluating a series of 293 consecutive sentinel lymph nodes from 293 patients. (12) Assay results were compared to intraoperative histologic examination of the entire sentinel lymph node performed on serial frozen sections that were H&E stained (with IHC when deemed necessary). All of the interval tissue not examined histologically was subjected to the assay. Seventy-two (24.6%) of the sentinel lymph nodes were involved with histologically identifiable metastases. The assay was positive in 67 sentinel nodes; in 56 cases, the results correlated with positive histology, whereas, in 11 cases, the histologic examination of the sentinel lymph node did not show evidence of metastatic disease, even with the addition of IHC. Five of the 11 possible false positive cases were further analyzed with additional tumor mRNA markers, and two of five (40%) were confirmed to be positive (true positives). The assay correctly identified 98.1% of macrometastases and 25% of micrometastases. Overall concordance with histopathology was 90.8%, with sensitivity of 77.8%, specificity of 95%, positive predictive value of 83.6%, and negative predictive value of 92.9%.
Mansel et al. prospectively examined 124 sentinel lymph nodes from 82 breast cancer patients, with 50% of each node analyzed by the GeneSearch assay and compared to H&E and IHC results. (13) The assay correctly identified all six patients with sentinel lymph node macrometastatic disease and two of three with micrometastatic disease. Two of four sentinel nodes positive by the assay but negative by histology turned out to contain isolated tumor cells. Overall concordance with histology was 93.9%, with a sensitivity of 88.9%, specificity of 94.6%, positive predictive value of 66.7%, and negative predictive value of 98.6%. No patient management decisions were based on the assay results.
Veys and colleagues reported 18 months of experience with the GeneSearch assay at their institution. (14) From November 2006 to January 2008, 253 consecutive patients with early-stage breast cancer (tumor less than 2 cm and clinically negative axillary lymph nodes) were treated with breast-conserving surgery and sentinel lymph node biopsy. Of 435 nodes, 295 highly radioactive nodes (68%) from 253 patients were analyzed intraoperatively with the GeneSearch assay, and the results were compared to postoperative histology. The lymph nodes were submitted in their entirety, with alternating sections submitted for the GeneSearch assay and standard postoperative histology (which at their institution consisted of at least one H&E section and additional H&E sections plus IHC if the initial H&E section was negative for tumor). Overall concordance for the GeneSearch assay with histopathology was 93%, with 87% sensitivity and 94% specificity. The sensitivity of the assay was dependent on the size of the metastasis with 89%–100% of macrometastases detected by the assay versus 70%–80% of micrometastases. Lymph node metastases were detected in 52 of the 253 patients by the assay versus 45 by standard histology. Thirteen percent of cases with metastases at least 0.2 mm in size detected by postoperative histology were negative by the assay. The percentage of patients with a positive assay but negative histology was 6% (n=13). These 13 patients underwent full axillary lymph node dissection based on the GeneSearch assay results, and two of the 13 were found to have non-sentinel lymph node metastases. No non-sentinel lymph node metastases were observed in the cases with histology-positive but assay-negative sentinel lymph nodes (n=5). Based on this, the authors did not consider assay-positive but histology-negative cases to be false positives.
The National Cancer Institute (NCI) Clinical Trials Database shows one ongoing prospective, multicenter phase III trial (GeneSearch breast lymph node assay China Registration Study). (15) The primary objective is to compare GeneSearch to permanent pathological sectioning to evaluate the clinical sensitivity and specificity in detecting axillary sentinel lymph node metastases in breast cancer patients. The secondary objective is to evaluate the positive and negative predictive value of the test when used in the detection of axillary node metastases. Estimated enrollment is 540 patients (NCT00869674). In 2010, Liu and colleagues reported the results thus far of this phase III prospective clinical feasibility study of the GeneSearch breast lymph node assay in 158 sentinel lymph nodes from 97 patients in China. (16) Alternating slabs from the sentinel lymph nodes were prepared for intraoperative breast lymph node assay testing. The results were compared to intraoperative imprint cytology and postoperative permanent section histopathology which consisted of examining alternating 1.5 to 3 mm slabs of the nodes by H&E. Overall, 31 of the 97 patients (32%) had sentinel lymph node metastases identified by histology, 20 of which were macrometastases (>2 mm) and 11 of which were micrometastases (0.2-2.0 mm). All of the patients with macrometastases were identified with the breast lymph node assay, and six of 11 (54.5%) of the sentinel lymph nodes with micrometastases were detected by the assay. Overall, the breast lymph node assay, compared with permanent section histopathology, had a sensitivity of 84%, specificity of 95.5%, positive predictive value of 90%, negative predictive value of 93%, and overall agreement of 92%. There were five cases of negative breast lymph node assay/histology positive and three cases with positive breast lymph node assay/histology negative. Eighty-six patients underwent complete axillary lymph node dissection after sentinel lymph node biopsy in the same surgery or in a second surgery. Non-sentinel lymph node metastases were detected in 16 (18.6%) patients, 14 of which were macrometastases and two of which were micrometastases. The breast lymph node assay was positive in the sentinel lymph nodes of 66.7% of patients who were non-sentinel-lymph-node-positive and positive in 25.8% of patients without further axillary involvement. The phase III trial authors agree that breast lymph node assay may be a viable alternative for the standard intraoperative procedures used for metastases detection, especially in early stage breasts cancer patients. Otherwise, as of December 2010, no other active phase III trials using molecular methods for the intraoperative assessment of sentinel lymph nodes in patients with breast cancer were identified.
A smaller study of 59 patients was reported earlier in 2010 by Tafe et al. (17) Of the 59 patients, the assay determined 43 as true negative, eight as true positive, one as false-negative, three as false-positive, and four as invalid. A larger study reported later in 2010 by Cutress et al. of 254 consecutive patients, where a total of 491 sentinel lymph nodes were evaluated. The intraoperative assay showed positivity of metastatic cells in 78 patients. (18) There was 100% detection of macrometastases within the sentinel nodes examined by GeneSearch. Overall concordance between histological status, including micrometastases and GeneSearch analysis, was 95% (sensitivity 96%, specificity 95%). Additional studies are in process in China, where the authors report the potential clinical application still requires further evaluation of larger number of cases.
Funasako and colleagues evaluated the clinical application of the GeneSearch assay in one Japanese institution in 117 patients with 204 sentinel lymph nodes. (19) One-half of each node was examined with the GeneSearch assay and the other half by H&E and IHC for pancytokeratin. H&E staining identified metastases in 31 of 204 sentinel lymph nodes (15.2%). A total of 173 sentinel lymph nodes without metastases detected by H&E staining were stained with IHC and an additional six sentinel lymph nodes were found to have metastases, all of which were isolated tumor cells. The sensitivity of the assay correlated with H&E and IHC 96% for macrometastases, 60% for micrometastases, and 56% for isolated tumor cells. Ten sentinel lymph nodes from ten patients were positive with the breast lymph node assay only, with no evidence of metastatic disease by H&E or IHC.
Visser et al. compared a quantitative cytokeratin 19 (CK19) mRNA one-step nucleic acid amplification technique (OSNA-CK19) to histologic staining (H&E and IHC) in 346 axillary lymph nodes from 32 patients, using one-half of each node for each method. (20) Sixty-one nodes were positive and 267 were negative by both methods. Three cases were positive by histology but negative by OSNA-CK19. Fifteen samples were negative by histology but positive by OSNA-CK19. Seven of the 15 cases were positive for other epithelial markers by RT-PCR and/or Western blot, suggesting that they were true-positive results. Overall concordance with histology was 94.8% and 96.8% after exclusion of the seven discordant cases. Sensitivity was 95.3% and specificity was 94.7% before and 97.1% after the discordant case investigation.
Veys and colleagues additionally retrospectively assessed the possible use of the breast lymph node assay in estimating the size of nodal metastases and the risk of metastatic disease in non-sentinel lymph nodes, as the size of the metastasis in the sentinel lymph node may predict non-sentinel lymph node metastases. (21) Between 2006 and 2008, 367 consecutive patients with clinically node-negative early stage (tumor size <2cm) breast cancer were treated with breast-conserving surgery and sentinel lymph node biopsy at one European institution. The breast lymph node assay was performed intraoperatively and if the assay results were positive in the sentinel lymph node, a full axillary lymph node dissection was performed. If the tumor size was intraoperatively determined to be greater than 2 cm, a full lymph node dissection was also performed (n=58) despite sentinel lymph node negativity. Permanent section sentinel lymph node examination consisted of at least one H&E section from all 2 mm lymph node sections not used for the breast lymph node assay. If no tumor was found on these H&E sections, additional sections were taken and alternatively stained with H&E and IHC until all nodal material was exhausted. Sentinel lymph node positivity was defined as metastasis larger than 0.2 mm. Pathologists examining the permanent section histology were blinded to the breast lymph node assay results. Seventy-eight sentinel lymph nodes were positive (72 with the assay, 62 by histologic examination with 17 cases breast lymph node positive/histology negative and seven cases breast lymph node negative/histology positive). Breast lymph node positivity was found in 19.6% (72/367) of patients versus 17% (62/367) assessed as positive by histologic evaluation. A total of 128 (35%) completion axillary lymph node dissections were performed, and residual metastases were found in 19 (14.8%). Eighteen of 19 of the axillary lymph node-positive cases were from patients with a sentinel lymph node positive with the breast lymph node assay and 16 from patients with sentinel lymph node metastasis detected by histology. The sensitivity of the assay to determine sentinel lymph node status was 89%, with a specificity of 94.5% and a negative predictive value of 97.5%. For the 78 positive sentinel lymph nodes (either by assay, histology or both), the levels of mammoglobin and CK 19 expression were compared to the size of the metastases as measured by histology. The correlation observed between metastasis size and the level of expression of mammoglobin and CK 19 genes was reported as having a p value of 0.62 and 0.64, respectively. The authors suggest that most of the cases with discrepant results between the assay and histology were micrometastases or had borderline expression of both assay gene markers, suggesting sampling effect.
Schem and colleagues reported results comparing one-step nucleic acid amplification (OSNA) to routine histopathologic investigation in 343 non-sentinel axillary lymph nodes in 93 breast cancer patients. (22) Lymph nodes were derived from completion axillary dissections performed because of a previously positive sentinel lymph node, or because the patient had a clinically positive lymph node. Lymph nodes were sampled with alternate slices allocated to the OSNA method or to histologic workup at five levels through the node. Of the 343 nodes, 211 were negative by both methods (which included two cases with isolated tumor cells) and 104 samples were positive with both methods. Discordant results were observed in 28 nodes, with two cases of OSNA negative/histology positive cases (both micrometastases) and 26 cases that were OSNA positive/histology negative. Discordant samples were subjected to further investigation including additional histologic workup, and Western Blot and quantitative real-time polymerase chain reaction (RT-PCR) on a different section of the lymph node. If these results gave the same result as the OSNA assay, they were not considered to be discordant cases. After discordant case investigation was performed, both of the OSNA negative or histology positive cases and 11 of the 26 OSNA positive or histology negative samples showed similar results to the OSNA assay. The authors no longer considered these to be discordant cases, and the concordance rate was 95.5% with a sensitivity of 100% and a specificity of 96.5% (before exclusion of these cases, concordance, sensitivity, and specificity were 91.8%, 98.1%, and 90.8%, respectively).
A letter to the editor regarding this study commented on several shortcomings, including that quantitative analysis of tumor is not possible using the authors’ methods because no calibration experiments were performed for the OSNA assay, that there is lack of information about the reproducibility of the test, and importantly, that the study suffers from a lack of gold standard to evaluate the sensitivity and specificity of the technique to detect tumor cells. (23) The letter states that the current gold standard is histologic proof of tumor, and that if this had been accepted as the gold standard in the study, an intolerable rate of discordance would have been the result, with a false positive rate of 7.3% and a false negative rate of 1.2%. The letter also questioned the evidence to support the authors’ justification for discordant results to be the result of sampling bias.
National Comprehensive Cancer Network Guidelines:
National Comprehensive Cancer Network (NCCN) Guidelines acknowledge the revised cancer staging manual by the American Joint Committee on Cancer (January 2003, sixth edition), which addresses the increasing use of novel pathology diagnostic techniques, and the addition of identifiers to indicate the use of sentinel lymph node molecular pathology techniques in staging a patient. (24) However, the NCCN makes no recommendations as how to incorporate molecular testing of a sentinel lymph node into clinical practice.
As highlighted in a recent editorial, the ongoing difficulties with using molecular techniques to detect metastases in sentinel lymph nodes include:
- the uncertainty of the clinical significance of RT-PCR-positive but histologically and IHC negative sentinel lymph nodes;
- the issue of possible false positives with a test as sensitive as RT-PCR;
- the exact size of the metastasis cannot be determined because the tissue is digested in preparation for RT-PCR; and
- the possibility that the assay is detecting small amounts of benign epithelial cells in the lymph node instead of metastatic carcinoma. (25)
What is still not clear is the clinical utility of using molecular methods to detect sentinel lymph node metastases in making patient management decisions. Thus, the coverage position of the medical policy remains unchanged.
The one clinical trial in the NCI Clinical Trials Database has been suspended. (26) The GeneSearch Breast Lymph Node Assay trial was a Phase VI post-market, prospective study designed to assess, under clinical use conditions, the assay turn-around-time from the time of node removal to the report of the assay result to the surgeon. The study was suspended in January 2010.
The NCCN continued to make no recommendations regarding molecular testing of a sentinel lymph node for breast cancer. (27)
A search of peer reviewed literature through March 2013 identified no new clinical trial publications or any additional information that would change the coverage position of this medical policy and remains experimental, investigational and unproven.
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