National Medical Policy

National Medical Policy Subject: Policy Number: Oncotype DX for Cancer NMP479 Effective Date*: January 2005 Updated: October 2017 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State s Medicaid Manual(s), publication(s), citation(s), and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation X Local Coverage Determination (LCD)* Molecular Diagnostic Tests (MDT): http://www.cms.gov/medicare-coveragedatabase/search/advanced-search.aspx Article (Local)* X Other Palmetto GBA. Jurisdiction 11 Part B Oncotype DX Colon Cancer Assay: http://www.palmettogba.com/palmetto/moldx.n sf/docscat/moldx%20website~moldx~browse %20By%20Topic~Covered%20Tests~8UMP3B8 280?open&navmenu=%7C%7C Palmetto GBA. MolDX. Oncotype DX Breast Cancer Assay Coding and Billing Guidelines (M00003): http://www.palmettogba.com/palmetto/moldx.n sf/docscat/moldx%20website~moldx~browse %20By%20Topic~Covered%20Tests~8SLME783 17?open&navmenu=%7C%7C Oncotype DX for Cancer Oct 17 1

None Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Policy Statement Oncotype DX The Oncotype DX (21 gene RT-PCR test) is considered medically necessary for members with breast cancer as a prognostic assay to identify who is most likely to respond to systemic chemotherapy when the following criteria are met: Newly diagnosed patients (within 6 months) whose breast cancer is stage I or II, Node-negative or with micrometastases (less than 2 mm in size) or with 1-3 involved ipsilateral axillary lymph nodes Tumor size 0.6 1 cm with moderate/poor differentiation or unfavorable features OR tumor size larger than 1 cm; Hormone (estrogen or progesterone) receptor-positive Human epidermal growth factor receptor (HER-2) negative who are considering treatment with adjuvant endocrine therapy (e.g. tamoxifen or aromatase inhibiters), and the results of this test is being considered with other factors such as staging, grading, and other tumor marker analyses along with the results of the Oncotype DX test that are expected to play a significant role in patient management The NCCN (2009) guidelines indicate that the Oncotype Gene Expression Profile may be considered in conjunction with other clinical information in determining treatment of breast cancer when the breast cancer is hormone receptor positive, HER2 negative and the following is present: Histology is ductal, lobar, mixed or metaplastic, and pt1, pt2 or pt3 and pn0, pn1mi (< 2mm axillary node metastasis), and Tumor is 0.6 1.0 cm poorly differentiated or unfavorable features (i.e. angiolymphatic invasion, high nuclear grade, or high histologic grade) or tumor is > 1cm. Not Medically Necessary Oncotype Dx is considered not medically necessary for node positive breast cancer unless specified as above, male breast cancer, and all other indications. Oncotype DX DCIS Assay Oncotype DX for Cancer Oct 17 2

Health Net, Inc. considers the Oncotype DX DCIS Assay to predict the risk of local recurrence of ductal carcinoma in situ (DCIS) and/or an invasive local carcinoma at 10 years following breast-conserving surgery, investigational. At this time, there is a paucity of data regarding the validity and clinical utility of this test. Oncotype DX Colon Cancer Assay Health Net, Inc. considers Oncotype DX colon cancer assay not medically necessary at this time. There is no evidence to determine if the assay improves clinical decision making, treatment selection, or patient outcomes. Clinical validation in stage II and III patients from QUASAR and National Surgical Adjuvant Breast and Bowel Project (NSABP) trials showed that recurrence scores are prognostic for recurrence, disease free survival (DFS) and overall survival (OS) in stage II and III colon cancer, but are not predictive of benefit to adjuvant therapy. Oncotype DX Prostate Cancer Assay Please refer to Health Nets policy on Tumor Markers for Cancer for information about this test. Defintions Micrometastases (pn1mi) RS RT-PCR ER IVDMIA H&E IHC BCP LNN SLN ROC AJCC GTE QUASAR TS RS GICS MMR Tumor clusters or occult micrometastases, are defined as greater than 0.2 mm but less than or equal to 2 mm in diameter. Micrometastases to ipsilateral axillary lymph nodes are distinguished from isolated tumor cells on basis of size and histological evidence of malignant activity Recurrence Score. Results from the Oncotype DX gene panel are combined into a recurrence score. This predicts the likelihood of distant recurrence in pts with node negative, estrogen receptor positive breast cancer who were treated with tamoxifen alone. RS low (RS<18), RS intermediate (RS 18 30), and RS high (RS 31 Reverse transcription polymerase chain reaction is a highly reproducible laboratory process used to determine expression of the 21-gene panel used in the Oncotype DX test. This diagnostic test quantifies the likelihood of disease recurrence in women with early-stage breast cancer and assesses the likely benefit from certain types of chemotherapy. Oncotype DX was developed for women with early-stage invasive breast cancer who are ER+ and whose lymph nodes are negative Estrogen receptor In vitro diagnostic multivariate index assay Hematoxylin & eosin Immunohistochemistry Breast Cancer Profiling Lymph node negative Sentinel lymph node Receiver operator characteristic American Joint Committee on Cancer Genetic Test Evaluation Quick and Simple and Reliable Clinical Trial Predictive treatment score Recurrence score Gastrointestinal Cancers Symposium Mismatch repair Oncotype DX for Cancer Oct 17 3

IVDMA TA DMFS BCSS HR In Vitro Diagnostic Multivariate Assays Technology Assessments Disease Metastasis Free Survival Breast cancer specific survival Hormone receptor Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures have been replaced by ICD-10 code sets. Codes Related To This Policy ICD-9 Codes 174.0 Nipple and areola 174.1 Central portion 174.2 Upper-inner quadrant 174.3 Lower-inner quadrant 174.4 Upper-outer quadrant 174.5 Lower-outer quadrant 174.6 Axillary tail 174.8 Other specified sites of female breast, including ectopic sites, inner breast, lower breast, midline of the breast, outer breast, upper breast, and contiguous or overlapping sites of the breast whose point of origin cannot be determined 174.9 Female breast, unspecified 175.0 Malignant alignment neoplasm of nipple and areola of male breast V86.0 Estrogen receptor positive status (ER+) ICD-10 Codes C50.011-C50.929 Malignant neoplasm of breast C79.81 Secondary malignant neoplasm of breast D05.00-D05.02 Lobular carcinoma in situ of breast D05.80-D05.92 Other and unspecified type of carcinoma in situ of the breast Z17.0 Estrogen receptor positive status [ER+] Z85.3 Personal history of malignant neoplasm of breast C18.0-C18.9 Malignant neoplasm of colon C19 Malignant neoplasm of rectosigmoid junction C20 Malignant neoplasm of rectum C21.8 Malignant neoplasm of overlapping sites of rectum, anus and anal canal C78.5 Secondary malignant neoplasm of large intestine and rectum D01.0-D01.2 Carcinoma in situ of colon, rectosigmoid junction, rectum Z85.038 Personal history of other malignant neoplasm of large intestine Z85.048 Personal history of other malignant neoplasm of rectum, Oncotype DX for Cancer Oct 17 4

rectosigmoid junction, and anus CPT Codes 81519 Oncology (breast), mrna, gene expression profiling by real-time RT-PCR of 21 genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as recurrence score. 84999 Unlisted chemistry procedure 88299 Unlisted cytogenetic study HCPCS Codes S3854 Gene expression profiling panel used in the management of breast cancer treatment (No longer covered by AMA CPT 2016) Breast Cancer Oncotype 21 gene RT-PCR assay Scientific Rationale - October 2015 The NCCN recently updated the Clinical Practice Guidelines in Oncology Guidelines for Breast Cancer (V3.2015) Breast Cancer indicating that the Oncotype 21 gene RT-PCR assay recurrence score can be considered in select patients with 1-3 involved ipsilateral axillary lymph nodes to guide the addition of combination chemotherapy to standard hormone therapy. This is based on a study by Albain et al (2010) who investigated the ability of the Oncotype recurrence score to determine the prognosis of node-positive(n+) women (n=227) treated with tamoxifen alone and those who might not benefit from anthracycline-based chemotherapy. The study included postmenopausal women with axillary node-positive (1 3 vs. 4 nodes) breast cancer and either ER-positive or PR-positive tumors. Patients were randomized to treatment with tamoxifen alone for five years (n=148; 94 with 1-3 positive nodes) or to treatment chemotherapy followed by tamoxifen (CAF-T) (n=219; 133 with 1 3 positive nodes). Patients in this subset had a slightly lower number of positive nodes and smaller tumor size (< 2 cm [n=46], 2 5 cm [n=94], > 5 cm [8]) compared to the parent trial, and 11.7% were HER2 positive. The samples were analyzed using the RT-PCR Oncotype assay. The recurrence score was significantly prognostic in the tamoxifen-only group (p=0.006). No benefit was identified in CAF-T patients with a recurrence score < 18 (p=0.97). There was however, an improvement in diseasefree survival for those with a high recurrence score 31 (p=0.033). The recurrence score by treatment interaction was significant only in the first five years (p=0.029), but the cumulative benefit was present at ten years. The results of the study suggested that patients with a low recurrence score and 1 3 involved axillary lymph nodes did not benefit from anthracycline-based chemotherapy, but those with a higher recurrence score had major benefit, independent of the number of positive nodes. October 2013 NCCN Clinical Practice Guidelines in Oncology on Breast Cancer (version 3.2013) consider the 21 gene RT-PCR assay as an option when evaluating patients with primary tumors characterized as 0.6 to 1.0 cm with unfavorable features or >1 cm, and node-negative, hormone-receptor positive, and HER2-negative (category 2A). In this circumstance, the recurrence score may be determined to assist in estimating likelihood of recurrence and benefit from chemotherapy. NCCN states further, Unplanned, retrospective subset analysis from a single randomized clinical trial in post-menopausal, axillary lymph node (ALN)-positive, ER- Oncotype DX for Cancer Oct 17 5

positive breast cancer found that the 21-gene RT-PCR assay may provide predictive information for chemotherapy benefit in addition to Tamoxifen. Patients with a high score in the study benefited from chemotherapy, whereas patients with a low score did not appear to benefit from the addition of chemotherapy regardless of the number of positive lymph nodes. Patient selection for assay use remains controversial. The TAILORx and RxPONDER trials are being conducted to determine if there is additional benefit from adjuvant chemotherapy in addition to endocrine therapy for intermediate-risk patients (as assessed by the gene based assays). Chen et al (2013) investigated whether patient, tumor, or practice characteristics drive its use and explored Oncotype DX RS and chemotherapy use in subgroups. Patients with ESBC with documented estrogen receptor-positive, lymph nodenegative, human epidermal growth factor receptor 2-negative tumors registered within McKesson Specialty Health's iknowmed electronic health record were included. Patient and practice characteristics by region and size were analyzed. The association between Oncotype DX RS value and use of chemotherapy were assessed. The study included 6,229 patients. Of these, 1,822 (29%) had an Oncotype DX RS result. Test use was 36%, 38%, 34%, 25%, and 6%, respectively, in patients age 45, 46-55, 56-65, 66-75, and 76 years; 33%, 25%, and 9% in patients with Eastern Cooperative Oncology Group performance status of 0, 1, and 2; 7%, 9%, 25%, 38%, 27%, and 10% in T1mic, T1a, T1b, T1c, T2, and T3 tumors; and 26%, 32%, and 33% for grades 1, 2, and 3 tumors. Of the 1,822 patients with available Oncotype DX RS, adjuvant chemotherapy use was 6%, 42%, and 84% in the low-, intermediate-, and high-risk groups. Investigators concluded patients who were younger, had better ECOG performance status, or had higher grade tumors were more likely to undergo RS testing. It appears that the RS test may have influenced the decision about whether to administer adjuvant chemotherapy: a low RS score was associated with lower chemotherapy use and a high RS score was associated with higher chemotherapy use. May 2012 Pending the results of prospective studies, the NCCN (2012) notes: The panel considers the 21 gene RT-PCR assay (i.e., Oncotype DX 21) as an option when evaluating patients with primary tumors characterized as 0.6 to 1.0 cm with unfavorable features or > 1 cm and node-negative, hormone receptor positive and HER2 negative (category 2A). In this circumstance the recurrence score must be determined to assist in estimating likelihood of recurrence and benefit from chemotherapy (category 2B). The panel emphasized that recurrence scores should be used for decision making only in the context of other elements of risk stratification for an individual patient. All recommendations involving the use of recurrence scores in treatment decision making are categorized as 2B. NCCN Categories of Evidence and Consensus: 2A - Based upon lower level evidence, there is uniform NCCN consensus that the intervention is appropriate 2B - Based upon lower level evidence, there is NCCN consensus that the intervention is appropriate Ductal Carcinoma in Situ (DCIS) Oncotype DX for Cancer Oct 17 6

Scientific Rationale - Initial Review October 2012 Ductal carcinoma in situ (DCIS), is a noninvasive early form of breast cancer (stage 0) that can progress and become invasive. According to the National Comprehensive Cancer Network (NCCN) guidelines on breast cancer (2012), the treatment of DCIS, includes lumpectomy plus radiation (category1); total mastectomy, with or without reconstruction (category 2A); lumpectomy alone followed by observation (category 2B). The NCCN notes there is no evidence that survival differs between the three treatment options. Decreased rates of local recurrence following lumpectomy have been observed in randomized trials with the addition of whole breast irradiation. Although randomized trials evaluating the effectiveness of total mastectomy in DCIS have not been performed, mastectomy is a highly effective strategy to decrease risk of local recurrence. The option of lumpectomy alone should be considered only in cases where the patient and the physician view the individual risks as low. According to the NCCN guidelines, tamoxifen treatment may be considered as a strategy to reduce the risk of ipsilateral breast cancer recurrence in women with ERpositive DCIS treated with breast-conserving surgery (category 1 for those undergoing breast-conserving surgery followed by radiation therapy; category2a for those undergoing excision alone). The benefit of tamoxifen for ER negative DCIS is not known. Genomic Health Inc. recently introduced a new version of the Oncotype DX assay for predicting cancer recurrence in patients with ductal in situ carcinoma (DCIS) breast cancer the Oncotype DX DCIS. According to Genomic Health Inc., the Oncotype DX DCIS is the first clinically validated genomic assay to provide an individualized prediction of the 10-year risk of local recurrence (DCIS or invasive carcinoma) to help guide treatment decision-making in women with ductal carcinoma in situ treated by local excision, with or without tamoxifen. The NCCN does not address the Oncotype DX test for DCIS in the 2012 Breast Cancer guidelines. The Oncotype DX DCIS assay uses 12 of the 21 genes included in the original Oncotype DX assay and a different algorithm from the original assay to combine the results of RT-PCR gene expression analysis to provide a Recurrence Score between 0 and 100 for DCIS. A study by the Eastern Cooperative Oncology Group (ECOG) describing the development and validation of the Oncotype DX DCIS assay was presented at the San Antonio Breast Cancer Symposium in December 2011. Researchers collected the Oncotype DX results from 327 of the women included in the original E5194 clinical trial. Using a new formula, the researchers calculated a DCIS Score to predict the likelihood of cancer returning within 10 years of the initial DCIS diagnosis. The researchers tested how well the DCIS Score predicted the recurrence rate for these women to see whether it was a good measure of future recurrence. Of the women included in the study, 75 percent were classified low risk, 14 percent intermediate risk and 11 percent high risk. When the DCIS Score was compared to rate of recurrence for these three groups, the researchers found a relationship that was statistically significant, or unlikely to have happened by chance. This suggests the DCIS Score is a good measure of possible recurrence. The study has yet to be published Scientific Rationale: Update -October 2015 There is a continued lack of evidence in the published medical literature to assess this technology and no recommendation by the NCCN at this time. Oncotype DX for Cancer Oct 17 7

October 2013 Solin et al (2013) reported for women with ductal carcinoma in situ (DCIS) of the breast, the risk of developing an ipsilateral breast event (IBE; defined as local recurrence of DCIS or invasive carcinoma) after surgical excision without radiation is not well defined by clinical and pathologic characteristics. The Oncotype DX breast cancer assay was performed for patients with DCIS treated with surgical excision without radiation in the Eastern Cooperative Oncology Group (ECOG) E5194 study. The association of the prospectively defined DCIS Score (calculated from seven cancer-related genes and five reference genes) with the risk of developing an IBE was analyzed using Cox regression. All statistical tests were two-sided. There were 327 patients with adequate tissue for analysis. The continuous DCIS Score was statistically significantly associated with the risk of developing an IBE (hazard ratio [HR] = 2.31, 95% confidence interval [CI] = 1.15 to 4.49; P =.02) when adjusted for tamoxifen use (pre-specified primary analysis) and with invasive IBE (unadjusted HR = 3.68, 95% CI = 1.34 to 9.62; P =.01). For the pre-specified DCIS risk groups of low, intermediate, and high, the 10-year risks of developing an IBE were 10.6%, 26.7%, and 25.9%, respectively, and for an invasive IBE, 3.7%, 12.3%, and 19.2%, respectively (both log rank P.006). In multivariable analyses, factors associated with IBE risk were DCIS Score, tumor size, and menopausal status (all P.02). Investigators concluded the DCIS Score quantifies IBE risk and invasive IBE risk, complements traditional clinical and pathologic factors, and provides a new clinical tool to improve selecting individualized treatment for women with DCIS who meet the ECOG E5194 criteria. Colon Cancer Scientific Rationale - Initial The Oncotype DX colon cancer test, the first multigene expression test developed to assess the risk for recurrence in patients with stage II disease, has only been available for commercial use since January 21, 2010. The 12-gene diagnostic test has been proposed to predict individual recurrence risk in stage II colorectal cancer patients following surgery. It uses a technology similar to that in the 27-gene Oncotype DX breast cancer test, which is already in clinical use. Following surgical removal of colon cancer, the cancer is referred to as Stage II if the final pathology report shows that the cancer has penetrated the wall of the colon into the abdominal cavity, but does not invade any of the local lymph nodes and cannot be detected in other locations in the body. Approximately 60-75% of patients with Stage II colon cancer have no evidence of cancer recurrence following treatment with surgery alone. However, 25-40%, or the remainder of patients with Stage II colon carcinoma, do experience recurrence. Typically, cancer recurs because there are small amounts of cancer that had spread outside the colon and were not removed by surgery. These cancer cells cannot be detected with any of the currently available tests. Undetectable areas of cancer outside the colon are referred to as micrometastases. The presence of micrometastases causes the relapses that follow surgical treatment. An effective treatment is needed to eliminate micrometastases and improve cure rates of Stage II cancer. Efforts are currently underway to find such a therapy. Treatment for Stage II colon cancer may consist of surgery, radiation, chemotherapy and/or targeted therapy (i.e. drugs which act by a different mechanism than chemotherapy to target tumor cells). Multi-modality treatment, which is treatment using two or more techniques, has been recognized as an important approach for Oncotype DX for Cancer Oct 17 8

increasing a patient's chance of cure or prolonging survival. In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. Circumstances unique to each patient's situation may influence how these general treatment principles are applied and whether the patient decides to receive treatment. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. Stage II colon cancer can be further divided into two stages, Stage IIA and Stage IIB. In Stage IIA, the tumor has grown through the outermost layers of the colon but is confined to the colon. In Stage IIB, the tumor has grown through the colon wall and has extended to adjacent tissues or organs. In both stages, there are no lymph nodes containing tumor cells and no distant metastases. Scientific Rationale - Update October 2015 The National Comprehensive Cancer Network (v3.2015) states that the information from multigene panels such as Oncotype can further inform the risk of recurrence over other risk factors, but are not predictive of benefit to adjuvant therapy. HAYES (2015) states there is limited quality evidence to assess the analytical validity, clinical validity, and clinical utility for estimating recurrence risk in patients with stage II or III colon cancer. Scientific Rationale Update October 2014 Srivastava et al. (2014) completed a prospective multicenter study in which stage IIA colon cancer patients were enrolled in 17 centers. Patient tumor specimens were assessed by the RS test (quantitative reverse transcription-polymerase chain reaction) and mismatch repair (immunohistochemistry). For each patient, the physician's recommended postoperative treatment plan of observation, fluoropyrimidine monotherapy, or combination therapy with oxaliplatin was recorded before and after the RS and mismatch repair results were provided. Of 221 enrolled patients, 141 patients had T3 MMR-P tumors and were eligible for the primary analysis. Treatment recommendations changed for 63 (45%; 95% confidence interval: 36%-53%) of these 141 T3 MMR-P patients, with intensity decreasing for 47 (33%) and increasing for 16 (11%). Recommendations for chemotherapy decreased from 73 patients (52%) to 42 (30%), following review of RS results by physician and patient. Increased treatment intensity was more often observed at higher RS values, and decreased intensity was observed at lower values (p =.011). Compared with traditional clinico-pathological assessment, incorporation of the RS result into clinical decision making was associated with treatment recommendation changes for 45% of T3 MMR-P stage II colon cancer patients in this prospective multicenter study. Use of the RS assay may lead to overall reduction in adjuvant chemotherapy use in this subgroup of stage II colon cancer patients. Per NCCN (Version 1.2015) on Colon Cancer: In summary, the information from these tests (eg., Oncotype DX, ColDx, and the ColoPrint) can further inform the risk of recurrence over other risk factors, but the panel questions the value added. Furthermore, there is no evidence of predictive value in terms of the potential benefit of chemotherapy to any of the available multigene assays. The panel believes that there are insufficient data to recommend the use of multigene assays to determine adjuvant therapy. Per Sanoff (UpToDate, 2014): Oncotype DX for Cancer Oct 17 9

Gene expression arrays such as a 12-gene recurrence score assay (i.e., Oncotype DX Colon Cancer Assay), an 18-gene classifier (ColoPrint), or a 13- gene classifier (ColoGuideEx), classifies based upon microrna expression, as well as presence of circulating tumor cells by molecular methods. The Oncotype DX Colon Cancer Assay is marketed by Genomic Health. How the recurrence score should be integrated with other known prognostic markers for routine care is uncertain. The benefit of adjuvant therapy for patients with stage II colon cancer remains controversial. Data from randomized trials and meta-analyses indicate that if there is benefit for 5-FU-based chemotherapy therapy in patients with resected stage II disease, that it does not exceed an absolute improvement in five-year survival of 5 percent. Insufficient numbers of patients have been accrued to determine whether there is a statistically significant smaller benefit that is clinically meaningful. Scientific Rationale Update October 2013 NCCN Clinical Practice Guidelines in Oncology on Colon Cancer (Version 1.2014) reported, Oncotype Dx colon cancer assay (Genomic Health, Inc.) quantifies the expression of 7 recurrence-risk genes and 5 reference genes as a prognostic classifier of low, intermediate, or high likelihood of recurrence. Clinical validation in patients from QUASAR and National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trials showed that recurrence scores are prognostic for recurrence, disease free survival (DFS), and overall survival (OS) in stage II and III colon cancer, but not predictive of benefit to adjuvant chemotherapy. For the low, intermediate, and high recurrence risk groups, recurrence at 3 years was 12%, 18% and 22%, respectively. Multivariate analysis showed that recurrence scores were related to recurrence independently from TNM staging. MMR status, tumor grade, and number of nodes assessed in both stage II and III disease. The NNCN guidelines also addressed other multigene assays also being investigated (e.g., ColoPrint, ColDx). Per the NCCN guidelines, The information from these tests can further inform the risk of recurrence over other risk factors, but the panel questions the value added. Furthermore, there is no evidence of predictive value in terms of the potential benefit of chemotherapy to any of the available multigene assays. The panel believes that there is insufficient data to recommend the use of multigene assays to determine adjuvant therapy. Scientific Rationale - Update May 2011 Oncotype DX for colon cancer was initially developed in four studies that Genomic Health conducted in conjunction with the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Cleveland Clinic. A total of 761 genes from 1851 patients with stage II colon cancer were analyzed, and 18 genes were identified as having the potential to predict the likelihood of cancer recurrence and response to chemotherapy, according to the researchers. The 18-gene assay was validated by testing tumor tissue from 1436 patients who participated in the QUASAR (Quick and Simple and Reliable) clinical trial. In addition to the QUASAR study, 2 new clinical trials appear to provide additional support for Oncotype DX. Both studies were presented at the recent 2010 Gastrointestinal Cancers Symposium (GICS) in Orlando, Florida. Gray et al. (2010) used data from the QUASAR trial to assess the prognostic value of nodal assessment in conjunction with other variables, including the previously validated 12-gene colon cancer recurrence score. The researchers found that both the number of nodes Oncotype DX for Cancer Oct 17 10

examined and the recurrence score were independent predictors of recurrence in stage II colon cancer following surgery. Both should be considered when assessing individual recurrence risk, they note, and the results are consistent with the National Comprehensive Cancer Network's recommendation that 12 or more nodes be examined as a target for nodal assessment (GICS abstract 331). O'Connell et al. (2010) conducted a study to gain a better understanding of the biological similarities and differences between stage II and III colon cancer, in order to improve clinical practice and trial design. The researchers compared pathologic markers and gene expression by stage in the 4 colon cancer studies that were initially conducted to develop the 12-gene recurrence score (GICS abstract 280). The authors noted above compared pathologic markers and the expression of 375 genes in patients with stage II and stage III disease, and found that the majority of the 375 genes and the recurrence score showed no significant interaction with stage. There were also similar patterns of gene expression by stage. Although differences were identified between the two cancer stages for some tumor characteristics, there is a similarity between stages for the recurrence score and the vast majority of genes analyzed. The range for determining recurrence risk is not as high in the colon cancer test as it is in the Oncotype DX for breast cancer. However, for stage II disease, it may be promising to have an objective gene profile to determine the risk. The assay will not be helpful in determining a treatment regimen for patients with stage II colon cancer. Predictive and prognostic biomarkers offer a potential means to personalize cancer medicine, although many reach the market-place before they have been validated, and their adoption is often hindered by variable clinical evidence. It remains uncertain at this time, how the recurrence score related to colon cancer, should be integrated with other known prognostic markers for routine care. National Cancer Comprehensive Network (NCCN, 2011) There is no mention of Oncotype DX in the Guidelines on Colon Cancer. Kelley et al. (2011) completed a case study that provides a structured review of the clinical evidence supporting four contemporary biomarker tests in colorectal cancer: K-Ras and B-Raf mutation analyses, mismatch repair protein testing, and the Oncotype DX Colon Cancer Assay. All four tests have been evaluated for guideline inclusion by the NCCN Guidelines Panel for Colon Cancer. The results of this case study shows a significant variability in the level of clinical evidence associated with these tests. In the cases of B-raf and mismatch repair protein testing, the available evidence is also inconsistent as it pertains to the specific NCCN Guideline recommendation. Based on this uncertainty in the evidence base, the authors conclude that expert clinical judgment, experience, and consensus may be more heavily weighted than published clinical trial data in the evaluation of new personalized medicine biomarker tests. Potential implications of this conclusion and future directions for research are discussed. In summary, the Oncotype DX colon cancer test, the first multigene expression test developed to assess the risk for recurrence in patients with stage II disease, has recently become available for commercial use, since January 21, 2010. FDA approval is not required for Oncotype DX for colon cancer, but this test must be performed in CLIA-certified lab. Few prospective studies have been conducted on the clinical utility of the Oncotype DX colon cancer assay and there is no evidence to determine if the assay improves clinical decision making, treatment selection, or patient outcomes, at this time. Oncotype DX for Cancer Oct 17 11

Professional Organizations The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2009) reported that they found adequate evidence regarding the association of the Oncotype DX Recurrence Score with disease recurrence and adequate evidence for response to chemotherapy. The EWG found adequate evidence to characterize the association of MammaPrint with future metastases, but inadequate evidence to assess the added value to standard risk stratification, and could not determine the population to which the test would best apply. The evidence was inadequate to characterize the clinical validity of the Quest H:I Test. The EGAPP Working Group reported that they found no evidence regarding the clinical utility of the MammaPrint and Quest H:I Ratio tests, and inadequate evidence regarding Oncotype DX. The EGAPP Working Group noted that these technologies have potential for both benefit and harm. National Cancer Comprehensive Network (NCCN) (2010) Another gene approach is the 21 gene assay using reverse transcription polymerase chain reaction (RT-PCR) on RNA isolated paraffin-embedded breast cancer tissue (i.e. Oncotype DX). Paik et al. (2004, 2006) completed two retrospective analyses of two trials ( NSABP B-14 and B-20) performed in women with hormone receptor-positive, axillary lymph node-negative invasive breast cancer, this assay system was able to quantify risk of recurrence as a continuous variable (i.e. Oncotype DX Recurrence Score) and to predict responsiveness to both tamoxifen and CMF or Methotrexate/5- fluorouracil/leukovorin chemotherapy. A recent comparison of simultaneous analyses of breast cancer tumors using 5 different gene expression models indicated that 4 of these methods (Including MammaPrint and Oncotype DX) had similar predictions of clinical outcomes. Currently two prospective randomized clinical trials (i.e. TAILORx and MINDACT) are addressing the use of Oncotype DX and MammaPrint respectively, as predictive and/or prognostic tools in populations of women with early-stage lymph nodenegative breast cancer. Pending the results of prospective trials, the Panel considers Oncotype DX as an option when evaluating patients with primary tumors characterized as 0.6-1.0 cm with unfavorable features or >1cm, and node-negative, hormone receptor-positive, and HER2 negative (category 2B). In this circumstance the recurrence score may be determined to assist in estimating the likelihood of recurrence and benefit from chemotherapy. The Panel emphasizes that the recurrence score should be used for decision making only in the context of other elements of risk stratification for an individual patient. The use of gene expression array data which also incorporate additional predictive biomarkers (i.e. Oncotype DX Recurrence Score) may provide additional predictive information beyond anatomic staging and determination of ER/PR and HER2 status. Assessment of the role of gene expression array technology is difficult because of the retrospective nature of the studies, the evolution of chemotherapy and hormone therapy regimens, and the overall more favorable prognosis of patients with lymph node-negative disease compared with those enrolled in the historically-controlled clinical trials. Some NCCN institutions consider performing Oncotype DX assay to further refine risk stratification for adjuvant chemotherapy for patients with nodenegative, ER-positive, HER2-negative breast cancers greater than 0.5cm, whereas others do not (category 2B). Per the NCCN categories of evidence and consensus: Category 2B notes the recommendation is based on any level of evidence but reflects major disagreement. Oncotype DX for Cancer Oct 17 12

Review History January 2005 Medical Advisory Council July 2006 Change in coverage for Medicare members December 2006 Change to medically necessary for all lines of business March 2007 Added aromatase inhibitors to policy statement Coding Updates. June 2010 Update. Revised Medicare guidelines per LCD on Oncotype DX Test Breast cancer prognosis. (L28287). Added various assays of genetic expression profiling as not medically necessary for all lines of business. Codes reviewed. October 2010 Added references to micrometastases May 2011 Update. Changed title to Oncotype DX for Cancer. Added Medicare Table with link to LCD and article. Added Oncotype DX for colon cancer as not medically necessary and MammaPrint for Breast Cancer as not medically necessary. May 2012 Update. No revisions. August 2012 Added link to Medicare article regarding Oncotype DX for colon cancer and link to Palmetto GBA. October 2012 Added Oncotype DX DCIS Assay to policy as investigational. October 2013 Update no revisions. Code updates. October 2014 Update no revisions. Code updates. January 2015 Added new CPT code October 2015 Removed and archived outdated information (prior to 2009) from Scientific Rationale. Removed information on other gene expression tests to place in Health Net s MammaPrint, Prosigna and other tests medical policy October 2016 Update. No revisions. Codes updated. October 2017 Update, No changes. Added current references This policy is based on the following evidence-based guidelines: 1. Bast RC, Ravdin P, Hayes DF, et al. 2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001 Mar 15;19(6):1865-78. Accessed at: http://www.jco.org/cgi/content/full/19/6/1865 2. Technology Evaluation Center. TEC Blue Cross Blue Shield. Gene Expression Profiling of Breast Cancer to Select Women for Adjuvant Chemotherapy. Assessment Program. Volume 22, No. 13. November 2007. 3. California Technology Assessment Forum (CTAF). Gene expression profiling as a guide for the management of early stage breast cancer. Technology Assessment. San Francisco, CA: CTAF; 2007. 4. Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology. American Society of Clinical Oncology 2007 recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007 Nov 20;25(33):5287-312. 5. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. V.2.2010. Updated Version 2.2011. Updated Version 1. 2012. Update Version 2.2012. Updated version 3.2013. Updated Version 3.2014. Updated Version 2.2016. Updated Version 2.2017 6. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Colon Cancer. V.2.2010. Updated Version 1.2012. Updated Version 3.2012. Updated Version 2.2013. Updated Version 1.2014. Updated Version 1. 2015. Updated Version 2.2016. Updated version 2.2017 Oncotype DX for Cancer Oct 17 13

7. Tice JA. The 70-Gene Signature (MammaPrint) As a Guide for the Management of Early Stage Breast Cancer. California Technology Assessment Forum. June 2, 2010. 8. Hayes. Genetic Test Evaluation (GTE) Overview. Oncotype DX Colon Cancer Assay for Risk of Recurrence of Colon Cancer. June 17, 2011. Updated July 26, 2013. Updated July 8, 2014. Updated October 15, 2015. 9. Hayes GTE Synopsis. Oncotype DX for Prognosis of Recurrence of Ductal Carcinoma In Situ (DCIS) Breast Cancer. March 2012. Updated March 2013. Updated March 20, 2014. 10. Hayes. Genetic Test Evaluation Overview. Oncotype DX DCIS Breast Cancer Test (Genomic Health Inc.). August 11, 2016. References Update October 2016 1. Alvarado M, Carter DL, Guenther JM, et al. The impact of genomic testing on the recommendation for radiation therapy in patients with ductal carcinoma in situ: a prospective clinical utility assessment of the 12-gene DCIS Score result. J Surg Oncol. 2015;111(8):935-940. 2. Mardekian SK, Bombonati A, Palazzo JP. Ductal carcinoma in situ of the breast: the importance of morphologic and molecular interactions. Hum Pathol. 2016;49:114-123. References Update October 2014 1. Lewis J, Borgen P. Breast Disease. Bope & Kellerman: Conn's Current Therapy 2014, 1st ed. 2013. 2. Burstein H. Adjuvant chemotherapy for hormone receptor-positive or negative, HER2-negative breast cancer. UpToDate. July 14, 2014. 3. Dowsett M, Sestak I, Lopez-Knowles E, et al. Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol 2013; 31:2783. 4. Goel G. J Gastrointest Cancer. 2014 Jul 3. [Epub ahead of print. ]Evolving Role of Gene Expression Signatures as Biomarkers in Early-Stage Colon Cancer. 5. Srivastava G, Renfro LA, Behrens RJ, et al. Prospective multicenter study of the impact of oncotype DX colon cancer assay results on treatment recommendations in stage II colon cancer patients. Oncologist. 2014 May;19 (5):492-7. doi: 10.1634/theoncologist.2013-0401. Epub 2014 Apr 7. 6. Yothers G, O'Connell MJ, Lee M, et al. Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin. J Clin Oncol. 2013 Dec 20;31(36):4512-9. doi: 10.1200/JCO.2012.47.3116. Epub 2013 Nov 12. References Update October 2013 1. Biroschak JR, Schwartz GF, Palazzo JP, et al. Impact of Oncotype DX on treatment decisions in ER-positive, node-negative breast cancer with histologic correlation. Breast J. 2013 May-Jun;19(3):269-75. 2. Carlson JJ, Roth JA. The impact of the Oncotype Dx breast cancer assay in clinical practice: a systematic review and meta-analysis. Breast Cancer Res Treat. 2013 Aug;141(1):13-22. 3. Chen C, Dhanda R, Tseng WY, et al. Evaluating use characteristics for the oncotype dx 21-gene recurrence score and concordance with chemotherapy use in early-stage breast cancer. J Oncol Pract. 2013 Jul 1;9(4):182-7. 4. de Boer RH, Baker C, Speakman D, et al. The impact of a genomic assay (Oncotype DX) on adjuvant treatment recommendations in early breast cancer. Med J Aust. 2013;199(3):205-8. Oncotype DX for Cancer Oct 17 14

5. Sgroi DC, Sestak I, Cuzick J, et al. Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncol. 2013 Sep 11. 6. Solin LJ, Gray R, Baehner FL, et al. A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ of the breast. J Natl Cancer Inst. 2013 May 15;105(10):701-10. 7. Stemmer SM, Klang SH, Ben-Baruch N, et al. The impact of the 21-gene Recurrence Score assay on clinical decision-making in node-positive (up to 3 positive nodes) estrogen receptor-positive breast cancer patients. Breast Cancer Res Treat. 2013 Jul;140(1):83-92. References Update October 2012 1. Geonomic Health Inc. Oncotype DX DCIS Breast Cancer Assay. Available at: http://www.oncotypedx.com/en- US/Breast/HealthcareProfessionalsDCIS/Overview/Overview References Update May 2012 1. Clark-Langone KM, Sangli C, Krishnakumar J, et al. Translating tumor biology into personalized treatment planning: analytical performance characteristics of the Oncotype DX Colon Cancer Assay. BMC Cancer. 2010;10:691. 2. Hayes DF. An overview of breast cancer. UpToDate. November 11, 2011. 3. Kelley RK, Van Bebber SL, Phillips KA, et al. Personalized medicine and oncology practice guidelines: a case study of contemporary biomarkers in colorectal cancer. J Natl Compr Canc Netw. 2011;9(1):13-25. References Update May 2011 1. Kelley RK, Van Bebber SL, Phillips KA, et al. Personalized medicine and oncology practice guidelines: a case study of contemporary biomarkers in colorectal cancer. Journal of National Comprehensive Network. 2011 Jan;9(1):13-25. 2. Compton CC. Pathology and prognostic determinants of colorectal cancer. UpToDate. April 29. 2010. 3. Sanoff HK. Adjuvant chemotherapy for resected stage II colon cancer. UpToDate. October 1, 2010. Updated June 11, 2014. 4. Nelson R. Oncotype DX Test for Recurrence Risk in Colon Cancer Now. Available. 2010. Medscape. 5. Albain KS, Barlow WE, Shak S, et al. Prognostic and predictive value of the 21- gene recurrence score assay in postmenopausal women with node-positive, estrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol. Jan 2010;11(1):55-65. 6. Gray RG, Quirke P, Handley K, et al. Correlation of number of nodes examined and the 12-gene colon cancer recurrence score with recurrence in stage II colon cancer patients from QUASAR. American Society of Clinical Oncology (ASCO). 2010. 7. O'Connell MJ, Lavery IC, Gray RG, et al. Comparison of molecular and pathologic features of stage II and stage III colon cancer in four large studies conducted for development of the 12-gene colon cancer recurrence score. American Society of Clinical Oncology (ASCO). 2010. 8. Clinicaltrials.gov. MINDACT (Microarray In Node-negative Disease May Avoid Chemotherapy): A Prospective, Randomized Study Comparing the 70-Gene Signature With the Common Clinical-Pathological Criteria in Selecting Patients for Adjuvant Chemotherapy in Breast Cancer With 0 to 3 Positive Nodes. 2010. Available at: http://clinicaltrials.gov/ct2/show/nct00433589?term=mindact&rank=1 Oncotype DX for Cancer Oct 17 15

9. Clinicaltrials.gov. Hormone Therapy With or Without Combination Chemotherapy in Treating Women Who Have Undergone Surgery for Node-Negative Breast Cancer (The TAILORx Trial). 2010. Available at: http://clinicaltrials.gov/ct2/show/nct00310180?term=tailorx&rank=1 10. Knauer M, Mook S, Rutgers EJ, et al. The predictive value of the 70-gene signature for adjuvant chemotherapy in early breast cancer. Breast Cancer Res Treat. Apr 2010;120 (3):655-661. 11. Kunz G. Use of a genomic test (MammaPrint) in daily clinical practice to assist in risk stratification of young breast cancer patients. Arch Gynecol Obstet. Apr 13 2010. 12. Mook S, Knauer M, Bueno-de-Mesquita JM, et al. Metastatic potential of T1 breast cancer can be predicted by the 70-gene MammaPrint signature. Ann Surg Oncol. May 2010;17(5):1406-1413. 13. Mook S, Schmidt MK, Weigelt B, et al. The 70-gene prognosis signature predicts early metastasis in breast cancer patients between 55 and 70 years of age. Ann Oncol. Apr 2010;21(4):717-722. 14. Ishitobi M, Goranova TE, Komoike Y, et al. Clinical Utility of the 70-gene MammaPrint Profile in a Japanese Population. Jpn J Clin Oncol. Jan 27 2010. 15. Straver ME, Glas AM, Hannemann J, et al. The 70-gene signature as a response predictor for neoadjuvant chemotherapy in breast cancer. Breast Cancer Res Treat. Feb 2010;119(3):551-558. 16. Watcher K. Gene assay helps predict recurrence in stage II colon cancer after surgery. May 18, 2009. 17. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: can tumor gene expression profiling improve outcomes in patients with breast cancer? Genet Med. 2009 Jan;11(1):66-73. 18. Goldhirsch A, Ingle JN, Gelber RD, et al. Thresholds for therapies: highlights of the St Gallen International Expert Consensus on the primary therapy of early breast cancer 2009. Ann Oncol. Aug 2009;20(8):1319-1329. 19. American Society of Clinical Oncology (ASCO). ASCO 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer. 20. Buyse M, Loi SA, van t VL, et al. Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst. Sept 6, 2006; 98 (17): 1183-1192. 21. van de Vijver MJ, He YD, van 't Veer LJ, et al. A Gene-Expression Signature as a Predictor of Survival in Breast Cancer. New England Journal of Medicine. 2002. References Update- October 2010 1. Singletary, S. Eva, Allred, Craig, Ashley, Pandora et al Revision of the American Joint Committee on Cancer Staging System for Breast Cancer 2002 J Clin Oncol 20:3628-3636. References Update June 2010 2. CMS. Centers for Medicare & Medicaid Services. LCD for ONCOTYPE DX Test - Breast Cancer Prognosis (L28287). Palmetta GBA. (Southern California). 2010. 3. CMS. Centers for Medicare & Medicaid Services. LCD for ONCOTYPE DX Test - Breast Cancer Prognosis (Prognosis (L28287). Palmetta GBA. (Northern California). 2010. 4. Hayes DF. Measurement of Prognostic Factors in Breast Cancer. March 6, 2009. 5. De Boer M, Van Deurzen CHM, et al, Micrometastases or Isolated Tumor Cells and the Outcome of Breast Cancer, The New England Journal of Medicine, Vol. 361, No. 7, August 13, 2009. Available at: http://content.nejm.org/cgi/reprint/361/7/653.pdf Oncotype DX for Cancer Oct 17 16