Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis In Patients With Breast Cancer
*Medicare has a policy.
The use of the 21-gene reverse transcriptase-polymerase chain reaction (RT-PCR) assay (i.e., Oncotype DX™) to determine recurrence risk for deciding whether or not to undergo adjuvant chemotherapy may be considered medically necessary in women with primary breast cancer, invasive breast cancer meeting ALL of the following characteristics:
All other indications for the 21-gene RT-PCR assay (i.e., Oncotype DX™), including determination of recurrence risk in invasive breast cancer patients with positive lymph nodes or patients with bilateral disease, are considered investigational.
Use of a subset of genes from the 21-gene RT-PCR assay for predicting recurrence risk in patients with noninvasive ductal carcinoma in situ (i.e., Oncotype DX™ DCIS) to inform treatment planning following excisional surgery is considered investigational.
The use of other gene expression assays (e.g., MammaPrint® 70-gene signature, Mammostrat™ Breast Cancer Test, the Breast Cancer Index, The Breast OncPx, NexCourse Breast IHC4, or PAM50 Breast Cancer Intrinsic Classifier) for any indication is considered investigational.
81504 Oncology (tissue of origin), micro-array gene expression profiling of >2000 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as tissue similarity scores.
There are no specific CPT codes for this laboratory test. Effective 1/1/06, an S code was designated for this test:
S3854 Gene expression profiling panel for use in the management of breast cancer treatment.
According to the American Society of Clinical Oncology-College of American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer, “a positive HER2 result is IHC staining of 3+ (uniform, intense membrane staining of >30% of invasive tumor cells), a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus or a FISH ratio (HER2 gene signals to chromosome 17 signals) of more than 2.2; a negative result is an IHC staining of 0 or 1+, a FISH result of less than 4.0 HER2 gene copies per nucleus, or FISH ratio of less than 1.8. Equivocal results require additional action for final determination.” (1)
Suggested Testing Management
The 21-gene RT-PCR assay (Oncotype DX™) should only be ordered on a tissue specimen obtained during surgical removal of the tumor and after subsequent pathology examination of the tumor has been completed and determined to meet the characteristics in the Policy above and the criteria below (i.e. the test should not be ordered on a preliminary core biopsy).
Note: See Policy section for additional criteria.
The 21-gene reverse transcriptase-polymerase chain reaction (RT-PCR) assay Oncotype DX™ should not be ordered as a substitute for standard estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 (HER2) testing.
Laboratory tests have been developed that detect the expression, via messenger RNA (mRNA) or protein, of many different genes in breast tumor tissue, and combine the results into a prediction of distant recurrence risk for women with early stage breast cancer. Test results may help providers and patients decide whether to include adjuvant chemotherapy in post-surgical management.
For women with early-stage breast cancer (i.e. cancer extends beyond the basement membrane of the milk ducts into adjacent tissue), adjuvant chemotherapy provides the same proportional benefit regardless of prognosis. However, the absolute benefit of chemotherapy depends on the baseline risk of recurrence. For example, women with the best prognosis have small tumors, are estrogen-receptor-positive, and lymph node negative. These women have an approximate 15% baseline risk of recurrence; approximately 85% of these patients would be disease free at 10 years with tamoxifen treatment alone and could avoid the toxicity of chemotherapy if they could be accurately identified. Conventional risk classifiers estimate recurrence risk by considering criteria such as tumor size, type, grade and histologic characteristics; hormone receptor status; and lymph node status. However, no single classifier is considered a gold standard, and several common criteria have qualitative or subjective components that add variability to risk estimates. As a result, more patients are treated with chemotherapy than can benefit. Better predictors of baseline risk could help women, who prefer to avoid chemotherapy if assured that their risk is low, make better treatment decisions in consultation with their physicians.
Recently, several groups have identified panels of gene expression markers (“signatures”) that appear to predict the baseline risk of invasive breast cancer recurrence after surgery, radiation therapy, and endocrine therapy (for hormone-receptor-positive tumors). Gene expression tests commercially available in the U.S. include: Oncotype DX™ (a 21-gene reverse transcriptase-polymerase chain reaction [RT-PCR] assay, Genomic Health); the 70-gene signature MammaPrint® (Agendia); Mammostrat® Breast Cancer Test (Clarient Diagnostic Services); the Breast Cancer IndexSM; a combination of the Molecular Grade Index (MGI) and the HOXB13:IL17BR Index (bioTheranostics); the BreastOncPx™ (Breast Cancer Prognosis Gene Expression Assay; LabCorp); NexCourse® Breast IHC4 (Geneoptix), and the PAM50 Breast Cancer Intrinsic Classifier (ARUP National Reference Laboratory). If these panels are more accurate than current conventional classifiers, they could be used to aid chemotherapy decision making when current guidelines do not strongly advocate its use, without negatively affecting disease-free and overall survival (OS) outcomes.
Oncotype DX™, using a slightly different algorithm to calculate results, is also marketed for patients with noninvasive, ductal carcinoma in situ (DCIS) to predict the 10-year risk of local recurrence (DCIS or invasive carcinoma). The stated purpose is to help guide treatment decision making in women with DCIS treated by local excision, with or without adjuvant tamoxifen therapy.
All tests except MammaPrint® are provided as laboratory-developed tests (LDTs) in Clinical Laboratory
Improvement Act (CLIA)-licensed laboratories operated by each company. These LDTs have not been cleared by the U.S. Food and Drug Administration (FDA); to date, FDA clearance is not required.
MammaPrint® has received 510(k) clearance for marketing by the FDA. All U.S. tests are performed at the CLIA-licensed Agendia clinical laboratory.
Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer services representative to determine whether there are any benefit limitations applicable to this service or supply.
In 2005, a TEC Assessment (2) summarized the evidence for 4 different gene expression profiling assays that were intended for use in identifying those patients at low risk of recurrence for whom adjuvant chemotherapy can be avoided. These were the 21-gene reverse transcriptase-polymerase chain reaction (RT-PCR) Oncotype DX™ assay, the 70-gene MammaPrint®, the 76-gene “Rotterdam signature” (Veridex), and a 41-gene signature reported by Ahr et al. The TEC Assessment concluded that because published evidence supporting clinical utility was not available, the evidence for all of the gene expression panels was insufficient to permit conclusions.
In 2008, the original TEC Assessment was updated (3) and limited to evaluation of the 3 gene expression profiles commercially available in the United States at that time (Oncotype DX™, MammaPrint®, and a new test called the Breast Cancer Gene Expression Ratio). The objective of the updated assessment was to determine for patients with early stage, node-negative breast cancer, whether the use of gene expression profiling improves outcomes when used to decide if risk of recurrence is low enough to forego adjuvant chemotherapy, compared to conventional risk assessment tools. The Assessment concluded that the evidence for the 21-gene expression assay (Oncotype DX™) met the TEC criteria, but that the evidence for the other two assays did not.
In 2010, a TEC Assessment addressed the use of the 21-gene expression assay (Oncotype DX™) in lymph node-positive breast cancer patients for the same indications as in the 2005 and 2008 Assessments. (4) The Assessment concluded that use of the 21-gene expression profile for selecting adjuvant chemotherapy in patients with lymph-node-positive breast cancer did not meet the TEC criteria.
This policy evidence review is based on the above TEC Assessments and on published evidence related to the assays listed in the Background.
The initial indications for the 21-gene expression profile (Oncotype DX™) were newly diagnosed invasive breast cancer in patients with stage I or II disease that is node-negative and estrogen-receptor (ER) positive, who would be treated with tamoxifen. Primary validation studies enrolled node-negative patients; this indication is reviewed first. More recently, Genomic Health has expanded their indication to include all stage II disease (tumor <2 cm with spread to axillary lymph nodes or 2-5 cm without lymph node involvement); this indication for lymph node-positive disease will be reviewed separate from lymph node-negative disease
Results from the Oncotype DX™ 21-gene expression profile are combined into a recurrence score (RS). Based on a study of analytic validity, tissue sampling rather than technical performance of the assay is likely to be the greatest source of variability in results. (5) The 21-gene expression profile was validated in studies using archived tumor samples from subsets of patients enrolled in already completed randomized controlled trials (RCTs) of early breast cancer treatment. Patients enrolled in the trial arms from which specimens were obtained had primary, unilateral breast cancer with no history of prior cancer and were treated with tamoxifen; tumors were ER-positive, most were human epidermal growth factor receptor 2 (HER2) negative, and in the case of at least 1 trial (6) multifocal tumors were excluded.
Lymph Node-negative Patients
Studies delineating the association between the 21-gene RS and recurrence risk are shown in the Table 1. (7-10) Results indicate strong, independent associations between the RS and distant disease recurrence or death from breast cancer. (8, 10) In secondary reclassification analyses of the Paik et al. data (7, 9), patient risk levels were individually classified by conventional risk classifiers, then re-classified by Oncotype DX™. Oncotype DX™ adds additional risk information to the conventional clinical classification of individual high-risk patients, and identifies a subset of patients who would otherwise be recommended for chemotherapy, but who are actually at lower risk of recurrence (average 7–9% risk at 10 years; upper 95% confidence level [CI] limits, 11–15%). The analysis does not indicate significant erroneous reclassification given known outcomes. Thus, a woman who prefers to avoid the toxicity and inconvenience of chemotherapy and whose Oncotype DX™ RS value shows that she is at very low risk of recurrence might reasonably decline chemotherapy. The lower the RS value, the greater the confidence the woman can have that chemotherapy will not provide net benefit; outcomes are improved by avoiding chemotherapy toxicity.
An additional study, in which samples from a RCT of ER-positive, node-negative breast cancer patients treated with tamoxifen versus tamoxifen plus chemotherapy were tested by Oncotype DX™, provides supportive evidence. RS high-risk patients derived clear benefit from chemotherapy, whereas the average benefit for other patients was statistically not significant, although the confidence intervals were wide and included the possibility of a small benefit. (6)
The 2008 Assessment concluded that the 21-gene RT-PCR assay Oncotype DX™ meets criteria for women similar to those in the validation studies, i.e. women younger than 70 years of age (or with a life expectancy greater than 10 years), with unilateral, non-fixed, ER-positive, node-negative (by full axillary dissection) invasive carcinomas, who treated with surgery (mastectomy or lumpectomy), radiation therapy, and tamoxifen. In 1 trial, patients in the experimental arm were also treated with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or myelofibrosis (MF) chemotherapy. Most (92%) patients were negative for HER2. (4)
Because clinical care for breast cancer patients has evolved since the original trials from which archived samples were acquired for assay validation, differences in evaluation and treatment regimens were considered. It was concluded that the 21-gene Oncotype DX™ meets the TEC criteria for the following women with node-negative invasive breast cancer:
Tzeng examined how women receive and incorporate the results of Oncotype DX™ using mailed survey and chart review. (19) About two-thirds of women believed they understood most or all of what they were told about their recurrence risk based on their test results; the majority who experienced test related distress had intermediate or high estimated recurrence risks by RS result. The objective, recalled, and perceived recurrence risks by women in the study were surprisingly similar, and 95% agreed that the test gave them a better understanding of their treatment options and chances of success. However, about one-third of women believed they understood only a moderate amount or less during these discussions. The study was limited in generalizability in that participants were mostly Caucasian, well-educated women who had health insurance and came from urban areas.
Several studies have been published regarding the impact of RS results on chemotherapy recommendations by medical oncologists. (20-27) In general, these studies report that comparing recommendations made prior to and revised after knowledge of RS results show that decisions change in about 25-40% of patients, most often from endocrine therapy plus chemotherapy to endocrine therapy alone. For example, in a retrospective reclassification analysis, Joh et al. found that inclusion of the Oncotype DX™ recurrence scores resulted in a 24.9% change in (after the fact) treatment recommendations, resulting in fewer patients projected to receive chemotherapy. (27) Hassett et al., evaluated registry data from the National Comprehensive Cancer Network (NCCN) Breast Cancer Outcomes Database Project focusing on women diagnosed for HR-positive stage I to III unilateral breast cancer during 2006-2008. Compared to women with Oncotype DX™-determined intermediate-risk cancer, women with Oncotype-determined high-risk cancers were more likely to receive chemotherapy (odds ratio [OR]: 12.0; 95% CI: 6.7 to 21.3) and women with low-risk cancers were less likely to receive chemotherapy (OR: 0.1; 95% CI: 0.1 to 0.2). (26) Some view these as evidence of clinical utility because more patients avoid the toxicity of chemotherapy (28); however there are no actual patient outcomes attached to these studies. In addition, none of the studies formalize and describe the way in which information is delivered to the patient, nor do they evaluate how patient preferences are incorporated into the final treatment decision. Lo et al. conducted a prospective multicenter study that examined both physician and patient treatment selection, as well as the impact of the RS result on patients’ anxiety, quality of life, and satisfaction with choice of treatment, but did not address the issue of whether results were described using a similar format for all patients so that they all had as close to the same information base as possible. (20)
Limitations of the current evidence, such as confirmation of optimal RS cutoff values for tamoxifen-treated and separately for AI-treated patients and recommendations for patients with intermediate RS values, are likely to be answered by the results of the ongoing Trial Assigning Individualized Options for Treatment (Rx), also known as TAILORx. (29)
The 2008 TEC Assessment also evaluated studies of Oncotype DX™ for use in predicting response to specific chemotherapy regimens and found the evidence insufficient for conclusions. These studies were reviewed, and the search was updated for this policy review (30, 31); no published studies were found that changed these conclusions.
Table 1. Summary of Oncotype DX RS and recurrence risk studies
Abbreviations: DRF, distant recurrence-free; ER, estrogen receptor; N, total number of patients; NR, not reported; RS, Oncotype DX recurrence score; K-M, Kaplan Meier; NSABP, National Surgical Adjuvant Breast and Bowel Project; RCT, randomized controlled trial; TAM, tamoxifen; NCCN, National Comprehensive Cancer Network (2004); Int/Intermed, Intermediate.
1Percentages are percent of total N.
2Estimated from graphs. Note that different outcomes were reported between Paik et al. 2004b and Bryant 2005 and could not be converted to similar outcomes with confidence intervals.
Lymph node-positive patients
Albain et al. evaluated samples from the Southwest Oncology Group Trial 8814, in which randomized node-positive, ER-positive patients treated with tamoxifen for 5 years were compared to those treated with cyclophosphamide, doxorubicin, fluorouracil (CAF) chemotherapy followed by tamoxifen (CAF-T) for 5 years. (32) Samples were available for determination of RS for 41% (n=148) and 39% (n=219) of the trial arms, respectively.
In this study, 10-year disease-free survival (DFS) and overall survival (OS) outcomes in the tamoxifen study arm differed by RS risk category (p=0.017 and 0.003, respectively), indicating that the RS is prognostic. When the 2 treatment arms were compared within RS risk categories, only patients in the high RS category significantly benefited from the addition of CAF to tamoxifen (for DFS, 42% [tamoxifen] vs. 55% [CAF-T], p=0.033; for OS, 51% [tamoxifen] vs. 68% [CAF-T], p=0.027), suggesting that RS is also predictive of response to chemotherapy.
A multivariable analysis of RS interaction with DFS, adjusted for number of positive nodes, was significant for the first 5 years of follow-up at p=0.029, and remained significant after adjusting for age, race, tumor size, progesterone receptor status, grade, p53, and HER2. However, the interaction was not significant (p=0.15) after adjusting for ER level (ER gene expression is a component of the 21-gene profile). Interaction results were similar for OS.
Dowsett et al. included a separate evaluation of node-positive patients in their examination of the ATAC Trial samples. (11) Of 306 node-positive patients, 243 had 1-3 involved nodes and 63 patients had 4 or more; these were not evaluated separately. Rates of distant recurrence at 9 years were 17% (95% CI, 12-24%), 28% (20-39%), and 49% (35-64%), respectively. It is not clear that the risk of distant recurrence in low-risk RS patients would be sufficiently low to forgo the choice of chemotherapy. The authors note that their study “did not directly evaluate the value of RS in predicting the benefit of chemotherapy”.
Goldstein et al. evaluated samples from the Eastern Cooperative Oncology GroupE2197 trial, which included patients with 0-3 positive lymph nodes and operable tumor greater than 1cm in size. (33) Patients were randomly assigned to doxorubicin plus cyclophosphamide or docetaxel plus 5 years of endocrine therapy; outcomes were not significantly different for the study arms. A case-control study of samples from this trial found that low-risk RS patients with 0-1 positive nodes had a recurrence risk of 3.3% (95% CI, 2.2-5%), and low-risk patients with 2-3 positive nodes had a recurrence risk of 7.9% (4.3-14.1%). RS was also a significant predictor of risk regardless of nodal status.
A previous study by Chang et al., reported that in women with locally advanced breast cancer treated with neoadjuvant docetaxel (n=97), a complete response was more likely in those with a high RS (p=0.008). (31) Gianni et al. studied 93 patients with locally advanced breast cancer who received neoadjuvant taxane chemotherapy, then post-surgery CMF treatment and tamoxifen (if ER-positive). (30) The authors reported that pathological complete response was more likely in patients with high RS results than with low RS results (p<0.01).
One study surveyed oncologists who are already ordering the 21-gene profile for lymph node-positive patients to determine the effect of the assay results on treatment recommendations and reported that approximately half changed their recommendations after receiving RS results, with 33% recommending endocrine therapy alone instead of endocrine plus chemotherapy. (35). However, only medical oncologists who were already using the assay (16% response rate) were surveyed, thus biasing the results. Finally, no outcomes were reported, providing no firm evidence of clinical utility.
Additional studies are necessary before it is possible to confidently withhold currently recommended chemotherapy (13) from lymph node-positive invasive breast cancer patients with low/intermediate RS results. The RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) trial, led by the Southwest Oncology Group, will enroll 4,000 women with RS equal to or less than 25 who have early stage, hormone receptor-positive, HER2-negative breast cancer involving 1 to 3 lymph nodes. Patients will be randomized to receive either chemotherapy with endocrine therapy or endocrine therapy alone. The primary trial outcomes are expected to be completed in December 2016 (http://clinicaltrials.gov/ct2/show/NCT01272037, last accessed January 30, 2013).
Patients with ductal carcinoma in situ (DCIS)
Ductal carcinoma in situ (DCIS) is breast cancer located in the lining of the milk ducts that has not yet invaded nearby tissues. It may progress to invasive cancer if untreated. The frequency of DCIS diagnosis in the U.S. has increased in tandem with the widespread use of screening mammography, accounting for about 20% of all newly diagnosed invasive plus noninvasive breast tumors. Recommended treatment is lumpectomy (mastectomy is also an option) with or without radiation treatment; post-surgical tamoxifen treatment is recommended for ER-positive DCIS, especially if excision alone is used. Because the overall rate of ipsilateral tumor recurrence (DCIS or invasive carcinoma) is about 25% at 10 years, it is believed many women are over treated with radiation therapy. Thus, accurate prediction of recurrence risk may identify those women who may safely avoid radiation.
The Oncotype DX™ DCIS test uses information from 12 of the 21 genes assayed in the standard Oncotype DX™ test for early breast cancer. According to the Oncotype website, analyses from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 study (8, 18) and the Habel et al. case-control study (10) were used to select genes that predict the risk of recurrence independent of tamoxifen treatment and ER status. Scaling and category cut-points were based on an analysis of DCIS Score results from a separate cohort of patients with DCIS; this study has not yet been published and is available only as a meeting abstract. (36) In a retrospective analysis of data and samples from patients in the prospective Eastern Cooperative Oncology Group E5194 study, the Oncotype DX™ Score for DCIS was compared with the 10-year recurrence risk in a subset of DCIS patients treated only with surgery and some with tamoxifen (n=327). DCIS Score was significantly associated with recurrence outcomes (HR: 2.34 per 50 units; 95% CI: 1.15, 4.59; p=0.02) whether or not patients were treated with tamoxifen. The standard Oncotype DX™ Score for early breast cancer was not associated with DCIS recurrence outcomes. This study is available as a meeting abstract but has not yet been published. (37) These studies address the development of the Oncotype DX™ DCIS Score and the clinical validity (association of the test result with recurrence outcomes). Whether women are better categorized as to their recurrence risk by the Oncotype DX™ DCIS Score compared with standard clinical indicators of risk has not yet been addressed. Full evaluation awaits publication of studies
MammaPrint®, also called the 70-gene signature, is a prognostic test for women with ER-positive or ER-negative, lymph node-negative breast cancer. The 2008 TEC Assessment (3) reviewed available studies (38-42) and found insufficient evidence to determine whether MammaPrint® is better than conventional risk assessment tools in predicting recurrence. Limited technical performance evaluation of the commercial version of the assay suggests good reproducibility. Recurrence rates of patients classified as low risk in available studies were 15–25%, likely too high for most patients and physicians to consider forgoing chemotherapy. Similarly, in 1 study, after Adjuvant! risk classification, patients reclassified as low risk by the 70-gene signature in either Adjuvant! risk group had 10-year disease-free survival (DFS) rates of 88–89%, with lower confidence limits of 74–77%. Patients reclassified as high risk had 10-year DFS rates of 69%, with lower confidence limits of 45–61% and upper confidence limits of 76–84%; receiver operating characteristic (ROC) analysis suggests only a small improvement with MammaPrint® classification compared to a conventional classifier. (38)
Studies of primarily node-negative disease
Because initial studies had been conducted on samples from younger patients (age younger than 61), Wittner et al. studied a cohort of 100 lymph-node-negative patients with a median age of 62.5 years and a median follow-up of 11.3 years (43). Twenty-seven low-risk patients by MammaPrint® had distant metastasis-free survival at 10 years of 100%. However, the study was underpowered, and patients were heterogeneous in terms of ER-positivity (73%), endocrine therapy (25%), and chemotherapy (23%) making conclusions difficult. An additional small study of samples from women with lymph node-negative disease suggested that the 70-gene signature was an independent and significant predictor of distant metastases but the small number of events limited conclusions. (44)
Original validation studies included patients with both node-negative and node-positive disease. Mook et al. retrospectively evaluated 148 consecutive, node-negative, post-menopausal patients, with primarily ER-positive tumors; only 18% received 2 years of adjuvant tamoxifen and none chemotherapy. (45) For the 61% with good prognosis, 5-year distant metastasis-free survival (DMFS) probability was 93% (95% CI:, 87-99%) whereas for those with poor prognosis DMFS was 72% (60-84%). The authors reported on concordance with Adjuvant! Online, but did not conduct a net reclassification analysis to determine additional impact of the MammaPrint® signature on outcomes.
The MicroarRAy PrognoSTics in Breast CancER (RASTER) study was designed to assess feasibility of implementation and impact on treatment decisions of the MammaPrint® 70-gene signature, as well as recurrence outcomes. Five-year follow-up results were presented at the 8th European Breast Cancer Conference. (46) The study followed 427 node-negative, early stage breast cancer patients who participated in the RASTER Study and had a 70-gene signature (MammaPrint®), which was available to help direct post-surgery treatment decisions, and which was compared to Adjuvant! Online. In the group that did not receive any adjuvant therapy, the patients classified as low risk by both the 70-gene signature and by Adjuvant! Online (n=88) had a DDFS of 95% (95%CI: 90-100%) and patients originally classified high risk by Adjuvant! Online but low risk by the 70-gene signature (n=70) had a similarly high DDFS of 100%. The results of patients receiving adjuvant therapy are presented in Table 2. The results suggest that MammaPrint® is a better prognostic classifier than standard clinical and pathological classifiers. However, the patient numbers are low and event numbers very low, making firm conclusions difficult. The results are also for 5-year recurrence, although because the study is not yet mature, 4-year recurrence rates would be more representative.
Table 2: Results of the RASTER Study, showing 5-year DDFS differences of a 70-gene signature Low classification vs. Low and High Adjuvant Online! Classification with and without Endocrine Therapy.
*DDFS, distant disease-free survival
This study concluded that by adding the 70-gene signature to standard guidelines used to select patients for adjuvant systemic therapy, a reduction of 29% in the use of adjuvant chemotherapy would be possible without impacting outcomes.
Studies of mixed or Node-Positive Disease
In a study of node-positive disease, Mook et al. evaluated 241 patients with 1-3 positive nodes and primarily ER-positive, HER2-negative tumors treated variably. (47) The 70-gene signature was a significant predictor of outcome. Reclassification analysis using Adjuvant! Online vs. MammaPrint® showed significant additional discrimination of outcomes by the gene signature, but all were confounded by heterogeneous patient treatment. This study also updated the results of 106 patients with 1-3 positive nodes from the validation study (19), reporting 98% (95% CI:, 94-100%) 10-year breast cancer-specific survival for good prognosis signatures vs. 64% (52-76%) for poor prognosis signatures; adjusted hazard ratio (HR): 3.63 (0.88–14.96), p=0.07. Based on these results, the ongoing MINDACT trial of MammaPrint® was enlarged to include patients with 1-3 positive lymph nodes. Pilot phase results of the MINDACT trial were published in 2011 and showed successful implementation of the biomarker-stratified trial design and compliance with chemotherapy treatment according to the risk of recurrence according to MammaPrint®. (48)
The 2012 I-SPY trial evaluated 237 patients with locally advanced disease (node-positive) by correlating imaging and MammaPrint® signatures with outcomes of pathologic complete response (pCR) and Recurrence Free Survival (RFS). (49) Despite having locally advanced disease, patients with 70-gene low-risk profiles tended not to respond to chemotherapy and to have good short-term RFS as shown in Table 3.
Table 3. Results of I-SPY 1: MammaPrint 70-gene signature results and trial outcomes
*Denotes significant proportional hazard ratio (likelihood ratio P <0.05). A value of 0.00 indicates that
there were no recurrences in this category among patients who had a pCR
Other studies comprise primarily small case series, and pooled re-analyses of subgroups from previously published retrospective studies. A pooled analysis of 964 patients from previously reported studies with pT1 tumors ( <2 cm) included 84% with ER-positive tumors, 68% with HER2-negative tumors (no HER2 information on 23%), 27% with node-positive disease, 68% given no adjuvant treatment and the rest treated variably. (50) In these patients, overall distant metastasis-free survival at 10 years was 87% (95% CI: 84-91%) for good prognosis patients and 72% (66-78%) for poor prognosis patients. The hazard ratio was 2.7 (95% CI: 1.88–3.88, p<0.001). Results are confounded by nodal status, HER2 status, and adjuvant therapy.
Kunz et al. conducted a pooled re-analysis of a subgroup of patients aged 35-55 years from previously published studies. (51) Patients were 75% ER-positive, 45% node-positive; 60% were untreated and the rest treated variably. The 70-gene signature categorized 39% of patients as good prognosis; for these patients the 10-year time to distant metastasis was 88% (95% CI: 84–92%). Bighin et al. reported difficulties in that nearly 25% of samples from 21 prospectively studied patients were not assessable by the 70-gene signature and that results lead to a change in clinical decision in less than 20% of cases. (52)
Finally, Retel et al. reported a cost-effectiveness analysis that simulated the course of events in a hypothetical cohort of 1000 patients aged 50 years with early, operable node-negative, ER-positive breast cancer, who are treated with 2.5 years of tamoxifen and 2.5 years of an aromatase inhibitor. The 70-gene signature was compared with Adjuvant! Online and St Gallen clinicopathologic classifiers. (53) While all three strategies were clinically equally effective, St Gallen was more costly and the 70-gene signature was most cost-effective when quality-adjusted life-years were taken into account.
The majority of MammaPrint® studies, including the early validation studies, suffered from confounding in heterogeneous sample populations. Subsequent pooled re-analyses of subpopulations controlled for one variable (e.g., nodal status), but confounding remained from other variables (e.g., treatment heterogeneity). Results for the 70-gene signature good prognosis patients have confidence intervals that extend into ranges that likely confer too much risk for patients and providers in the U.S. Because the test result is not a continuous numerical result, patients cannot view their result within the spectrum of good prognosis results and adjust their preferences accordingly. The recently presented Microarray Prognostics in Breast Cancer (RASTER) study represents an improved study design, and results suggest that MammaPrint may accurately re-classify early, node-negative breast cancer patients classified high risk for recurrence by clinical and pathological variables to low risk, such that chemotherapy may not be necessary. However, the study is not yet published, patient numbers and events are too low for firm conclusions, and follow-up is not yet sufficiently mature.
Breast Cancer IndexSM
The Breast Cancer Index is a simultaneous assessment of HOXB13:IL17BR Index and the MGISM (Molecular Grade Index). The 2008 TEC Assessment (3) reviewed available studies for the original component assays (54-58). There was insufficient evidence to determine whether the H/I Ratio is better than conventional risk assessment tools in predicting recurrence. Ten-year recurrence rates of patients classified as low risk in available studies were 17%–25%, likely too high for most patients and physicians to consider forgoing chemotherapy. The Molecular Grade Index is intended to measure tumor grade using the expression of 5 cell cycle genes, and to provide prognostic information in ER-positive patients regardless of nodal status.
Ma et al. evaluated MGI along with H/I in 93 patients with lymph node–negative tumors who received adjuvant hormone therapy and found that each index modified the other’s predictive performance. (59) High MGI was associated with significantly worse outcome only in patients with high H/I and vice versa. When the H/I Ratio and MGI were categorically combined into a single predictor, the estimates of 10-year distant metastasis-free survival were 98% (95% CI: 96-100%), 87% (77-99%), and 60% (47-78%) for the low, intermediate, and high-risk groups, respectively.
Jerevall et al. combined the H/I Ratio and MGI into a continuous risk model using 314 ER-positive, node-negative post-menopausal patients from the tamoxifen-only arm of a randomized controlled trial. (60) The continuous model was also categorized resulting in proportions of low, intermediate, and high-risk patients similar to those reported in the Ma et al. study. (59) This continuous predictor was tested in patients from the no adjuvant treatment arm (n=274) of the same clinical trial, with estimates of rates of distant metastasis at 10 years in the low, intermediate, and high risk groups of 8.3% (95% CI: 4.7–14.4), 22.9% (14.5–35.2) and 28.5% (17.9–43.6), respectively. The estimates of breast cancer-specific death were 5.1% (95% CI: 1.3–8.7), 19.8% (10.0–28.6) and 28.8% (15.3–40.2). An independent population of otherwise similar but tamoxifen-treated patients was not tested.
Jankowitz evaluated tumor samples from 265 ER-positive, lymph node (LN)-negative, tamoxifen-treated patients from a single academic institution’s cancer research registry. BCI categorized 55%, 21%, and 24% of patients as low, intermediate and high-risk, respectively, for distant recurrence. The 10-year rates of distant recurrence were 6.6% (95% CI: 2.3-10.9%), 12.1% (95% CI: 2.7-21.5%) and 31.9% (95% CI: 19.9-43.9) and of breast cancer-specific mortality were 3.8%, 3.6% and 22.1% in low, intermediate, and high-risk groups, respectively. In a multivariate analysis, BCI was a significant predictor of distant recurrence and breast cancer-specific mortality. In a time-dependent (10-year) ROC curve analysis of recurrence risk, the addition of BCI to Adjuvant! Online risk prediction increased maximum predictive accuracy in all patients from 66% to 76% and in tamoxifen-only treated patients from 65% to 81%. (59)
Mammostrat™ Breast Cancer Test
Mammostrat™ is an immunohistochemistry (IHC) test intended to evaluate risk of breast cancer recurrence in postmenopausal, node negative, ER-positive invasive breast cancer patients who will receive endocrine therapy and are considering adjuvant chemotherapy. The test employs 5 monoclonal antibodies to detect gene expression of proteins biologically independent of each other and not involved in cell proliferation, hormone receptor status, or growth/differentiation, thus potentially allowing integration with clinically routine biomarkers. A proprietary diagnostic algorithm is used to calculate a risk score and to classify patients into high-, moderate-, or low-risk categories.
One published study described the development of the assay but provides no information on technical performance (analytic validity). (62) In a validation study in an independent cohort, a multivariable model predicted 50%, 70%, and 87% 5-year DSF for patients classified as high, moderate, and low prognostic risk, respectively, by the test results (p=0.0008). (62) An additional study of the same trial samples used for Oncotype DX validation (NSABP B-14 and B-20 trials) found that among patients with early, node-negative breast cancer treated only with tamoxifen, those stratified by Mammostrat™ into low, moderate, and high-risk groups had recurrence-free survival estimates of 85%, 85%, and 73%, respectively. (63) Both low- and high-risk groups benefited significantly from chemotherapy treatment, but high-risk patients benefited to a greater degree. The moderate-risk group was not well-separated from the low-risk group and thus, moderate-risk results do not appear to provide clinically useful information. A test for an interaction between chemotherapy and the risk group stratification was not significant (p=0.13).
Bartlett et al. used Mammostrat™ on 1,540 of 1,812 patient samples from a consecutive cohort for which minimum 9-year outcomes were available. (64) The tested samples were from tamoxifen-treated patients; 568 of these were from node-negative patients treated only with tamoxifen and whose tumors were ER-positive. In the latter group, the distant recurrence rates at 10 years for low-, moderate-, and high-risk patients were 7.6% (95% CI, 4.6-10.5%), 16.3% (10.0-22.6%), and 20.9% (12.3-29.5%). In multivariable analysis, Mammostrat™ was not a significant predictor of recurrence-free survival in node-negative, ER-positive patients treated only with tamoxifen. However, when all patients (24% node positive, 20% tumors > 2.0 cm, 18% ER-negative, and 46% treated with chemotherapy) with complete Mammostrat™ data (n=1,300) were included in a multivariable analysis, Mammostrat™ scores were independent predictors of recurrence-free survival (p=0.0007). In exploratory analyses of various subpopulations (e.g. node-negative vs. node-positive, ER-negative), Mammostrat™ appeared to perform similarly in terms of identifying risk groups. However, numbers of subsets were small.
The BreastOncPx™ test is an reverse transcriptase-polymerase chain reaction (RT-PCR) test performed on formalin-fixed, paraffin embedded tissue that measures the gene expression of 14 genes associated with key functions such as cell-cycle control, apoptosis, and DNA recombination and repair. The results are combined into a metastasis score, which is reported to be associated with the risk of distant metastases in patients who are node-negative and estrogen-receptor positive.
Tutt et al. published information on the development and validation of the test (65); no information on analytic validity was provided. In order to develop a gene signature that was completely prognostic for distant recurrence and not confounded by treatment prediction, samples from untreated patients with early breast cancer were used. The training set (n=142) was derived from a cohort diagnosed with lymph node-negative, stage T1 and T2 breast cancer from 1975 to 1986; ER-positive samples from patients who had had no systemic treatment were selected for analysis. Fourteen genes were eventually selected as most prognostic of time-to-distant metastasis and were given equal weighting in a summary metastasis score (MS). Using a single cutoff, patients are separated into high and low-risk groups.
The 14-gene signature was validated on ER-positive samples (n=279) from a separate cohort of patients diagnosed with lymph node-negative primary breast cancer between 1975 and 2001. (65) The estimated rates of distant metastasis-free survival were 72% (95% CI: 64-78%) for high risk patients and 96% (95% CI: 90-99%) for low risk patients at 10 years follow up. Overall 10-year survival for high and low risk patients was 68% (95 CI: 61% to 75%) and 91% (95% CI: 84 to 95%), respectively. After adjusting for age, tumor size and tumor grade in a Cox multivariate analysis, the HRs for distant metastasis-free survival for the high versus low risk group were 4.02 (95% CI: 1.91-8.44) and 1.97 (95% CI: 1.28 to 3.04) for distant metastasis-free survival and overall survival, respectively. However, this difference in risk between groups was not maintained when the analysis was restricted to patients with tumors larger than 2 cm (p value for interaction 0.012).
ROC analysis of the continuous MS for distant metastasis and for death at 10 years, compared to Adjuvant! resulted in slightly higher area under the curves (AUCs) for the MS in each case: 0.715 vs. 0.661 for distant metastases, and 0.693 vs. 0.655 for death. MS was not added to Adjuvant! and compared to Adjuvant! alone.
NexCourse Breast IHC4
NexCourse Breast IHC4 evaluates the protein expression of ER/PR, HER2, and Ki-67 to provide a combined recurrence risk score. The assay technology uses quantitative image analysis to measure immunofluorescent signals, with results that can be combined in an algorithm to generate the recurrence risk score. The use of quantitative immunofluorescence is said to increase sensitivity, be more reproducible, and allow specific measurement of tumor cells. (66, 67)
Cuzick et al. evaluated 1,125 ER-positive patients from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial who did not receive adjuvant chemotherapy, already had the Oncotype DX™ Recurrence Score (RS) computed, and had adequate tissue for the IHC4 measurements.(68) Of these, 793 were node-negative and 59 were HER2-positive (but were not treated with trastuzumab). A prognostic model that combined the 4 immunohistochemical markers was created (IHC4). In a model combining either IHC4 or Oncotype DX™ RS with classical prognostic variables, the IHC4 score was found to be similar to the Oncotype Dx™ RS and little additional prognostic value was seen in the combined use of both scores. In a direct comparison the IHC4 score was modestly correlated with the Oncotype Dx™ RS (r=0.72); the correlation was similar for node-negative patients (r=0.68). As an example, for a 1-2 cm, node-negative poorly differentiated tumor treated with anastrozole, 9-year distant recurrence at the 25th versus 75th percentiles for IHC4 and Oncotype DX™ were 7.6% versus 13.9% and 9.2% versus 13.4%, respectively. The IHC4 score was validated in a separate cohort of 786 ER-positive women, about half of whom received no endocrine treatment. The IHC4 score was significant for recurrence outcomes (hazard ratio (HR) = 4.1; 95%CI: 2.5-6.8).
Barton et al. assessed the clinical utility of IHC4 plus clinicopathologic factors (IHC4 + C) by comparison with Adjuvant! Online and the Nottingham Prognostic Index (NPI). (69) The study prospectively gathered clinicopathologic data for consecutively treated postmenopausal patients (n=101 evaluable) with hormone receptor-positive, HER2-negative, lymph node-negative or positive with 1-2 nodes, resected early breast cancer. Of 59 patients classified as intermediate-risk group by the NPI, IHC4 reclassified 24 to low-risk and 13 to high-risk. IHC4 reclassified 13 of 32 Adjuvant! high-risk patients to intermediate-risk and 3 of 32 to low-risk. In addition, 15 of 26 Adjuvant! intermediate-risk patients were reclassified to low-risk. No Adjuvant! low-risk patients were reclassified high-risk.
PAM50 Breast Cancer Intrinsic Classifier
The initial development of the PAM50 breast Cancer Intrinsic Classifier was reported by Parker et al. (70) The authors developed a qRT-PCR test based on a panel of 50 genes to identify the breast cancer “intrinsic” subtypes luminal A, luminal B, HER2-enriched, and basal-like, and to generate risk-of-relapse scores in node-negative patients who had not had systemic treatment for their cancer. In an independent test set, the test using 3- categories of risk (low, intermediate, and high) was significantly prognostic (Log-rank p=0.0002).
Nielsen et al. compared the PAM50 classifier with standard clinicopathologic factors as represented by Adjuvant! Online and with models based on immunohistochemistry (IHC) for biomarkers of intrinsic subtypes. (71) The study used samples from patients diagnosed between 1986 and 1992 with ER-positive breast cancer, either higher-risk (e.g. with lymphovascular invasion) node-negative or node-positive disease, and treated with 5-years of tamoxifen but no adjuvant chemotherapy. In the node-negative population, Adjuvant! Online was inferior to all other biomarker models for predicting recurrence and disease-specific survival. A model including the PAM50 risk of recurrence gene expression signature that also incorporated the influence of proliferation and tumor size identified patients with a greater than 95% chance of remaining alive and disease-free beyond 10 years. A slightly different gene expression model best fit the node-positive population, but did not identify a sufficiently low-risk population that adjuvant hormone therapy would likely be considered sufficient.
Because the cohort used to generate the models evaluated in this study was biased toward higher-risk early breast cancers, it is likely not generalizable. Nor did the authors clearly identify a final model for clinical use. Rather, the authors outlined potential additional studies.
Cheang et al. determined PAM50 intrinsic subtypes for samples from a clinical trial randomizing premenopausal women with node-positive breast cancer to 2 different regimes of chemotherapy. The PAM50 intrinsic subtype for 476 tumors was correlated to relapse-free survival (RFS; P = 0.0005) and overall survival (OS; P < 0.0001). The HER2-enriched subgroup (22%) showed the greatest benefit from cyclophosphamide-epirubicin-fluorouracil (CEF) versus cyclophosphamide-methotrexate-fluorouracil (CMF), with absolute 5-year RFS and OS differences exceeding 20%. There was a less than 2% difference for non–HER2-enriched tumors (interaction test P = 0.03 for RFS and 0.03 for OS). Within clinically defined HER2-positive tumors, 79% (72 of 91) were classified as the HER2-enriched subtype by gene expression and this subset was associated with better response to CEF versus CMF (62% vs. 22%, P = 0.0006). There was no significant difference in benefit from CEF versus CMF in basal-like tumors.(72)
Test Comparison Studies
Fan et al. used 5 gene expression classifiers to evaluate a single set of samples from 295 women with stage I or II breast cancer, variable node involvement, and variable endocrine or chemotherapy treatment. (73) The classifiers included the 21-gene Recurrence Score, the 70-gene signature, the H/I ratio, and the intrinsic subtype classifier (similar to the commercially available PAM50). Most highly correlated were the 21-gene Recurrence Score and the 70-gene signature at a Cramer’s V of 0.6 (scale 0 to 1 with 1 indicating perfect agreement). More specifically, 81 of the 103 samples with a Recurrence Score of low or intermediate risk were classified as having a low risk 70-gene profile. Restricting the analysis to the 225 ER-positive samples slightly reduced the correlation. The analysis was not further restricted to node-negative patients, the present indication for both tests.
Espinosa et al. compared the 21-gene Recurrence Score (Oncotype DX™), the 70-gene signature (MammaPrint®), and the 2-gene ratio (H/I Ratio) in 153 patients with ER-positive breast cancer treated with adjuvant tamoxifen. (40) Thirty-eight percent of these patients were node-positive, and 63% were additionally treated with chemotherapy. Distant metastasis-free survival for the Recurrence Score profile was 98% for low-risk patients versus 81% intermediate risk versus 69% high-risk; for the 70-gene signature the estimates were 95% good prognosis versus 66% poor prognosis; and for the 2-gene ratio, 86% favorable versus 70% unfavorable. There was a good correlation between the 21-gene Recurrence-Score and the 70-gene signature (Cramer’s V=0.6). Slightly more variation in distant metastasis-free survival was explained by the combination of the 21-gene Recurrence score and either Adjuvant! Online (25.8+1.4) or the Nottingham Prognostic Index (NPI; 23.7+1.5) than by the combination of the 70-gene signature with Adjuvant! Online (23.1+1.2) or the NPI (22.4+1.3) but the differences were very small and any combination was significantly better than any test or clinicopathologic classifier alone.
Two recent papers compared the Oncotype DX™ and other gene expression profiles. Kelly et al. (74) evaluated Oncotype DX™ and PAM50 in 108 cases and found good agreement between the 2 assays for high and low prognostic risk assignment but PAM50 assigned about half of Oncotype DX™ intermediate risk patients to the PAM50 luminal A (low risk) category. Prat et al. evaluated several gene expression tests of interest including Oncotype DX™, PAM50 and MammaPrint® in 594 cases and found all predictors were significantly correlated (Pearson correlation range 0.36-0.79; P < 0.0001 for each comparison). (24)
Based on a study published in May 2008 that compared the Oncotype DX™ ER and PR results to traditional IHC results, (75) Genomic Health is now including the quantitative ER and PR component results in the Oncotype DX™ 21-gene profile report. The study reported 90% or better concordance between the2 assays but that quantitative ER by Oncotype DX™ was more strongly associated with disease recurrence than the IHC results. However, ER and PR analysis is traditionally conducted during pathology examination of all breast cancer biopsies, whereas Oncotype DX™ is indicated only for known ER-positive tumors, after the pathology examination is complete, the patient meets specific criteria, and patient and physician are considering preferences for risk and chemotherapy. Thus, Oncotype DX™ should not be ordered as a substitute for ER and PR IHC. Additionally, accepted guidelines for ER and PR testing outline standards for high-quality IHC testing and do not recommend confirmatory testing; thus the 21-gene RS should not be ordered to confirm ER/PR IHC results. Similarly, guidelines for HER2 testing specify IHC and/or fluorescence in situ hybridization (FISH) methods. (1) The HER2 component of the 21-gene assay has been shown in one large study to strongly correlate with FISH results, (76) but significant discrepancies have been noted in another. (77) As a result, and without evaluation and support from guidelines, it has been recommended that the 21-gene assay not be ordered to determine or confirm HER2. (78)
Clinical Input Received through Physician Specialty Societies and Academic Medical Center
In response to requests, input was received from 1 Physician Specialty Society and 4 Academic Medical Centers while this policy was under review in 2008. While the various Physician Specialty Societies and Academic Medical Centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the Physician Specialty Societies or Academic Medical Centers, unless otherwise noted. A clear majority of the reviewers agreed with the policy conclusions.
21-gene Recurrence Score (Oncotype DX™)
The assay is supported by strong evidence of clinical validity, that is, the recurrence score (RS) is strongly associated with risk of distant recurrence in women with breast cancer that is positive for hormone receptors, negative for HER2, and without lymph node involvement. Limited but sufficient evidence supports analytic validity and clinical utility in this population. Oncotype DX™ adds additional risk information to the conventional clinical classification of individual high-risk patients, and identifies a subset of patients who would otherwise be recommended for chemotherapy but who are actually at lower risk of recurrence (average 7–9% risk at 10 years; upper 95% confidence interval (CI limits: 11–15%). Thus, a woman who prefers to avoid the toxicity and inconvenience of chemotherapy and whose Oncotype DX™ RS value shows that she is at very low risk of recurrence might reasonably decline chemotherapy.
In similar women who are node-positive, the evidence is less clear that the risk of recurrence in low-risk RS patients is sufficiently low or that the benefit of chemotherapy is insufficiently large, to recommend avoiding otherwise currently recommended treatment. Additional studies are necessary and ongoing.
For women with ductal carcinoma in situ (DCIS), the use of a subset of genes from the 21-gene recurrence score (i.e., Oncotype DX™ DCIS) to predict recurrence and inform treatment planning post-excision, development and clinical validity studies have not yet been published to allow full evaluation. Moreover, no information is yet available on whether women are better categorized as to their recurrence risk by the Oncotype DX™ DCIS Score compared with standard clinical indicators of risk.
70-gene signature (MammaPrint®)
A large number of studies of clinical validity, and a few attempting to address the clinical utility of the 70-gene signature have been published. Several studies have pooled and re-analyzed subsets of previously published data in attempts to arrive at more homogeneous sample populations. Nevertheless, the studies of the 70-gene signature continue to suffer from confounding in heterogeneous sample populations. Pooled re-analyses of subpopulations may control for one variable (e.g. nodal status), but confounding remains from other variables (e.g. treatment heterogeneity). Results for the 70-gene signature good prognosis patients have confidence intervals that extend into ranges that likely confer too much risk for patients and providers in the U.S. Because the test result is not a continuous numerical result, patients cannot view their result within the spectrum of good prognosis results and adjust their preferences accordingly. The recently presented Microarray Prognostics in Breast Cancer (RASTER) study represents an improved study design, and results suggest that MammaPrint® may accurately re-classify early, node negative breast cancer patients classified high risk for recurrence by clinical and pathological variables to low risk, such that chemotherapy may not be necessary. However, the study is not yet published, patient numbers and events are too low for firm conclusions, and follow-up is not yet sufficiently mature.
Mammostrat™ Breast Cancer Test, Breast Cancer Index, BreastOncPx, Pam50 Breast Cancer Intrinsic Classifier, NexCourse Breast IHC4
The available evidence supporting these tests consists of clinical validity data showing that the test is independently and significantly associated with distant recurrence and that the test can identify a lower risk population of women with early, invasive breast cancer who may not need chemotherapy. In almost all cases, the test is not added to and compared with a standard clinicopathologic classifier such as Adjuvant!, nor were any reclassification analyses reported. The BreastOncPx validation study included an receiver operating characteristic (ROC) analysis comparing the test with Adjuvant!, but no clear evidence supporting clinical utility was available. NexCourse Breast IHC4 (immunohistochemical markers) was compared with standard clinicopathological prognostic classifiers in a reclassification analysis and was shown to accurately reclassify significant numbers of patients from high and intermediate risk to low risk, but numbers in the study were small and insufficient for conclusions.
Practice Guidelines and Position Statements
The 2011 National Comprehensive Cancer Network (NCCN) guidelines (13) indicate that Oncotype DX™ (termed the “21-gene RT-PCR assay”) is an option in breast cancer patients with the following characteristics:
The 2007 American Society of Clinical Oncology (ASCO) guidelines (79) indicate that “In newly diagnosed patients with node-negative, estrogen-receptor positive breast cancer, the Oncotype DX™ assay can be used to predict the risk of recurrence in patients treated with tamoxifen.” In 2009, the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer “considered the available multigene assays...and concluded that a validated assay should be taken into account as an adjunct to high-quality pathology phenotyping” if there was doubt about the clinical decision regarding chemotherapy, but did not name any specific assays. (80)
Neither the NCCN, nor the American Society of Clinical Oncology specifically support any indications for the use of MammaPrint®, Mammostrat™, Breast Cancer Index, BreastOncPx, or PAM50. (13, 79)
Medicare National Coverage
The Local Coverage Determination (Northern California) for Oncotype DX™ states that “The Oncotype DX™ test is covered for patients with estrogen-receptor positive, node-negative carcinoma of the breast, for patients with estrogen receptor positive micrometastases of carcinoma of the breast, and for patients with estrogen positive breast carcinoma with 1-3 positive nodes.” Results of the Oncotype DX™ test “are expected to play a significant role in management of the patient.” In addition, the test is not considered reasonable and necessary for care when more than six months have elapsed since diagnosis “because the association of the test with outcomes of delayed chemotherapy is not known”.
Because all Oncotype DX™ tests are performed in the Genomic Health clinical laboratory in northern California, the local coverage determination is a de facto national coverage determination.
Oncology (tissue of origin), microarray gene expression profiling of >2000 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as tissue similarity scores. (effective 01/01/14)
Unlisted multianalyte assay with algorithmic analysis
Malignant neoplasm of nipple and areola
Malignant neoplasm of central portion
Malignant neoplasm of upper-inner quadrant
Malignant neoplasm of lower-inner quadrant
Malignant neoplasm of upper-outer quadrant
Malignant neoplasm of lower-outer quadrant
Malignant neoplasm of axillary tail
Other specified sites of female breast
Breast (female), unspecified
Carcinoma in situ of breast
Malignant neoplasm of breast code range
Carcinoma in situ of breast code range
Estrogen receptor positive status [ER+]
Gene expression profiling panel for use in the management of breast cancer treatment
Type of Service
Place of Service
Add to Pathology/Laboratory - New Policy.
Replace policy - Policy updated with February 2005 TEC Assessment; policy statement wording changed for clarification; indications added to policy guidelines in case of exception being considered.
Replace policy - Policy updated with reference correction by adding Paik et al 2004 study (cited in TEC Assessment); S code added. No change to policy statement. Presenting to OAP 2/16/06.
Replace policy - Policy reviewed with literature search; reviewed and recommended by OAP for adoption on 7/25/06; no change in policy statement.
Replace policy - Policy updated with literature review; reference added. No changes in policy statement. Reviewed and recommended by OAP on May 24, 2007.
Cross Reference Update - No other changes.
Replace policy - Policy updated with literature review; references and text block for each section was extensively revised. Policy statement changed to indicate that use of Oncotype DX to determine recurrence risk for women who meet specific criteria may be considered medically necessary. Other indications for Oncotype DX or use of other gene expression markers are considered investigational. Reviewed and recommended by OAP on February 21, 2008.
Cross Reference Update - No other changes
Replace policy - Policy updated with literature search. Policy statement updated to include updated assays (Mammostrat and Aviari MGI) that are considered investigational. References added.
Replace policy - Policy updated with literature search. Policy statement added regarding Theros Breast Cancer Index and clarification regarding investigational status for lymph node-positive patients. References added.
Cross Reference Update - No other changes
Replace policy - Policy updated with literature review. The policy statement has been updated to include Mammostrat and Aviara MGI. Reviewed and recommended by OAP on August 19, 2010.
Replace policy – Policy updated with literature search; rationale revised extensively. Reference numbers 1, 4, 5, 16-24, 26, 29, 30, 32, 42-46, 53, 56-59, 61 added; no change to policy statements. ICD-10 codes added to policy.
Related Policies updated: policies 2.01.45, 2.01.55 and 7.01.09 removed, as these policies have been archived.
Policy renumbered to 12.04.36 (previously 2.04.36) and reassigned to new Genetic Testing category.
Update Related Policies – 2.04.37 has been added.
Replace policy. Policy updated with new statement that use of the 21-gene RT-PCR assay (Oncotype DX) test for patients with bilateral disease is considered investigational. NexCourse® Breast IHC4 is a new test that is added as investigational. Policy guidelines include information under the header of “Testing Management” that is moved from the policy section for usability. Rationale updated with literature review through October 2012. Reference numbers 24, 26, 27, 44, 46, 47, 59, 64-67, 70, 72-76 added, others renumbered or removed. Policy statement changed as noted. Remove Related Policies 6.01.510 and 8.01.516 as they were archived.
Coding update. CPT codes 83890 – 83913 deleted as of 12/31/12; CPT code 81200 – 81479 and 81599, effective 1/1/13, added to the policy.
Replace policy. Policy statement updated with addition of “ALL” of the following criteria. Added Oncotype DX™ DCIS is investigational. Rationale reorganized and updated with DCIS study information. Retained the Policy guidelines header of “Testing Management” that includes criteria moved from the policy section for usability. References renumbered or removed to match the rationale section revision. ICD-9 233.0 and ICD-10 D05.00-D05.92 added to codes table. Policy statement changed as noted.
Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).