Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis in Patients with Breast Cancer

POLICY NUMBER

A.2.04.36

DESCRIPTION

Laboratory tests have been developed to detect the expression, via messenger RNA, of different genes in breast tumor tissue and combine the results to determine prognosis in patients with breast cancer. Test results may help providers and patients decide whether to include adjuvant chemotherapy in the post-surgical management of breast cancer, to alter treatment in patients with ductal carcinoma in situ or triple-negative breast cancer (TNBC) (estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2), or to recommend extended endocrine therapy in patients who are recurrence-free at 5 years.

Newly Diagnosed Breast Cancer

Per the Centers for Disease Control, breast cancer is a disease in which cells in the breast grow out of control, and can be found in the lobules, ducts, and connective tissue. Breast cancer affects individuals of all races and ethnicities and sexes. New cases are highest among White women (137.9 per 100,000) followed by Black women (131.3 per 100,000). Rates of death from breast cancer, however, are highest among Black women (26.8 per 100,000) followed by Native Hawaiian or Other Pacific Islander women (20.5 per 100,000), and White women (19.4 per 100,000).

Breast cancer in men is rare, accounting for less than 1% of all breast cancer cases in the US. Still, 2,790 men will be diagnosed with breast cancer and 530 men will die from the disease in 2024. Black men have the highest breast cancer incidence (1.9 per 100,000) and mortality (0.5 per 100,000) of all racial and ethnic groups. Compared to women, men are more likely to be diagnosed with advanced (regional- or distant-stage) disease (48% vs. 31%), reflecting the absence of screening, as well as delays in diagnosis due to lack of awareness. The 5-year relative breast cancer survival rate is lower in men than women overall (84% vs. 91%, respectively) and for every stage of diagnosis.

Female Breast Cancer

The most common breast cancers are invasive ductal carcinoma and invasive lobular carcinoma. Less common types of breast cancer include Paget’s disease, medullary, mucinous, and inflammatory. In ductal carcinoma in situ (DCIS), the cancer cells are only in the lining of the ducts and have not spread to other tissues; DCIS may lead to invasive breast cancer. Most breast cancer diagnoses are female breast cancer diagnosed at a localized stage (confined to the primary site), with less diagnoses being regional (spread beyond the primary site or to regional lymph nodes) or distant (spread to other organs or remote lymph nodes). The Nottingham score is a histological scoring system reflecting the grade of breast cancers. It is a total of scores based on microscopic determination of tubule formation, nuclear pleomorphism, and mitotic activity with each given a score of 1 to 3. Thus, the lowest Nottingham score is 3 and the highest is 9, with higher values thought to predict more aggressiveness. Nottingham score of 3-5 is assigned Grade I, 6-7 assigned Grade II, and 8-9 assigned Grade III.

Most women with newly diagnosed breast cancer in the United States present with the early-stage or locally advanced (ie, nonmetastatic) disease. However, almost a third of women who are disease-free after initial local and regional treatment develop distant recurrences during follow-up. Current breast cancer treatment regimens involve systemic adjuvant chemotherapy, hormonal therapy, biologic therapy, or a combination, depending on patients’ baseline levels of recurrence risk, hormonal markers, and risk tolerance.

Women whose tumors are positive for human epidermal growth factor receptor 2 (HER2) should receive adjuvant therapy with a HER2-directed therapy (trastuzumab with or without pertuzumab). Decision-making about adjuvant biologic therapy for women with HER2-positive cancer is not discussed here. This policy focuses on 4 decision points:

1. The decision to pursue adjuvant chemotherapy following locoregional therapy, with or without neoadjuvant chemotherapy, based on the predicted risk of recurrence, for women who are hormone receptor–positive but HER2-negative. The use of adjuvant chemotherapy reduces the risk of breast cancer recurrence but carries risks of systemic toxicity. The risk:benefit ratio must be considered for each patient, with a higher likelihood of net health benefits for patients with a greater baseline predicted risk of recurrence. Some of the individual considerations are discussed below. HER2 expression independently confers an unfavorable prognosis, but assessing the independent effects of HER2 is complicated in the presence of targeted therapy; therefore, we focus specifically on patients without HER2 expression.

2. The decision to pursue extended adjuvant endocrine therapy from 5 to 10 years for women who are hormone receptor–positive but HER2-negative and who have survived without a recurrence for 5 years. For patients with hormone receptor–positive tumors, the use of adjuvant endocrine therapy (tamoxifen and/or an aromatase inhibitor [AI], with or without ovarian suppression) for 5 to 10 years after an initial diagnosis has support in clinical practice. Support for extended endocrine therapy beyond the initial 5 years is inconsistent across various guidelines. The guidelines from the National Comprehensive Cancer Network (v4.2024) include various recommendations and considerations, based on menopausal status at diagnosis and after 5 years of therapy, and on prior therapy history. The guidelines also note that the optimal duration of aromatase inhibitors is uncertain. The American Society for Clinical Oncology's updated guidelines (2018) vary based on recurrence risk and nodal status.

3. The decision to pursue adjuvant radiotherapy in women with ductal carcinoma in situ. Adjuvant radiotherapy reduces the risk of local recurrences but has not been shown to change the risk of distant recurrence or mortality. There may be a group of patients for whom the reduction in risk for local recurrence may not be large enough to justify the risks of radiotherapy.

4. The decision to pursue neoadjuvant chemotherapy in women with Triple-Negative Breast Cancer (TNBC). In women with TNBC, pathological complete response has been found to be heterogenous in the neoadjuvant setting and has been associated with prolonged overall survival. For example, although TNBC tends to be more aggressive than other breast cancer types and confers a less favorable prognosis, previous research has suggested that the 20% to 40% of women with TNBC who achieve pathological complete response may achieve a similar long-term survival prognosis as patients with non-TNBC breast cancers. This heterogeneity suggests that there may be subtypes of women with TNBC that significantly differ in their likelihood of response to neoadjuvant chemotherapy and differ in their risk:benefit treatment considerations.

Selection of Adjuvant Chemotherapy Based on Risk of Recurrence

An important part of treatment planning for women with breast cancer involves determining which patients could benefit from adjuvant cytotoxic chemotherapy. For example, for women with early-stage invasive breast cancer (i.e. cancer extending beyond the basement membrane of the mammary ducts into adjacent tissue), adjuvant cytotoxic chemotherapy consistently provides approximately a 30% relative risk reduction in 10-year breast cancer mortality regardless of patients' baseline prognosis. However, the absolute benefit of chemotherapy depends on the underlying or baseline risk of recurrence. Women with the best prognosis have tumors that are small, early-stage, estrogen receptor–positive, and lymph-node negative (Table 1 shows recurrence risk for estrogen receptor–positive cancers for patients followed in the International Breast Cancer Study Group).

Patients may have received no adjuvant treatment, or adjuvant tamoxifen and/or adjuvant chemotherapy. These women have an approximately 15%, 10-year risk of recurrence with tamoxifen alone, which means that approximately 85% of these patients could avoid the toxicity of adjuvant cytotoxic chemotherapy if they could be accurately identified. Conventional risk classifiers (eg, Adjuvant! Online) estimate recurrence risk by considering criteria such as tumor size, type, grade, and histologic characteristics; hormone receptor status; and the number of affected lymph nodes. Consensus guidelines for defining receptor status exist. However, no single classifier is considered a criterion standard. As a result, a substantial number of patients are treated with chemotherapy who fail to benefit. Better predictors of recurrence risk could help women's decision-making, some of whom may prefer to avoid chemotherapy if assured their risk is low.

Table 1. Effect of Nodal Involvement, Tumor Size, and Grade on Annual Recurrence Hazard in Estrogen Receptor–Positive Breast Cancers

SE: standard error.ª Number of events occurring within a time interval divided by the total years of follow-up during the interval accrued by patients at risk during the interval. Patients may have received no adjuvant treatment or have been treated with adjuvant tamoxifen and/or adjuvant chemotherapy.

Selection of Extended Endocrine Therapy

Randomized controlled trials have established that 5 years of tamoxifen improves mortality in women with hormone receptor–positive breast cancer. A 2011 individual patient data meta-analysis by the Early Breast Cancer Trialists' Collaborative Group, including 20 trials (total N=21,457 patients) found that 5 years of tamoxifen in estrogen receptor–positive disease reduced the relative risk of recurrences by almost 50% over 10 years; breast cancer mortality was decreased by 29% through 15 years.

Early randomized controlled trials of extended tamoxifen treatment (Tormey and colleagues [1996]; total N=194 patients), the National Surgical Adjuvant Breast and Bowel Project (Fisher and colleagues [2001]; total N=1172 patients), and the Scottish Cancer Trials Breast Group (Stewart and colleagues [2001]; total N=342 patients) had mixed findings. However, more recent available trial evidence suggests that 10 years of tamoxifen in pre- or postmenopausal women can be linked with improved survival (see Table 2).

These randomized controlled trials have shown that extended endocrine therapy decreases the risk of recurrence. The Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, which compared 5 and 10 years of tamoxifen, and the subsequent Long-term Effects of Continuing Adjuvant Tamoxifen to 10 Years versus Stopping at 5 Years (aTTom) trial (reported in abstract form) included women who were hormone receptor-positive who had completed 5 years of tamoxifen. Five years of extended tamoxifen was associated with improvements in breast cancer-specific mortality in both ATLAS and aTTom; however, only ATLAS showed improvements in overall survival (see Table 2).

Several trials have compared survival outcomes in women using extended Aromatase inhibitors vs placebo following several years of tamoxifen, and 2 trials compared the use of extended aromatase inhibitors for different durations (3 years vs 6 years and 2.5 years vs 5 years) (see Table 2). No differences in overall survival were detected between the aromatase inhibitor groups and the placebo groups. Differences in breast cancer-specific survival were inconsistent. Differences in disease specific survival and overall survival were not detected among patients receiving aromatase inhibitors for different lengths of time.

Adverse Events from Extended Endocrine Therapy

Adverse events from extended tamoxifen include increased risk of thromboembolic disease (deep vein thrombosis, pulmonary embolism) and endometrial cancer. The ATLAS trial reported relative risks of 1.9 (95% CI, 1.1 to 3.1) for pulmonary embolus and 1.7 (95% CI, 1.3 to 2.3) for endometrial cancer. Adverse events from extended aromatase inhibitors include musculoskeletal side effects (eg, carpal tunnel syndrome, bone pain, bone fractures). In meta-analyses comparing tamoxifen and aromatase inhibitors, results showed an increased risk in cardiovascular events with aromatase inhibitors relative to tamoxifen. Women treated with aromatase inhibitors have also experienced higher fracture rates compared with women treated with tamoxifen.

Table 2. Randomized Trials Evaluating Adjuvant Extended Endocrine Therapies for Hormone Receptor-Positive Breast Cancer

ABCSG: Austrian Breast and Colorectal Cancer Study Group; CI: confidence interval; DATA: Different Durations of Adjuvant Anastrozole Therapy; ER: estrogen receptor; HR: hazard ratio; IDEAL: Investigation on the Duration of Extended Adjuvant Letrozole; ITT: intention to treat; NCIC CTG: National Cancer Institute Clinical Trials Group; NS: not significant; NSABP: National Surgical Adjuvant Breast and Bowel Project; PR: progesterone receptor; RR: rate ratio; SALSA: Secondary Adjuvant Long-Term Study with Arimidex [anastrozole]; TAM: tamoxifen.

Male Breast Cancer

The current NCCN guidelines on the management of breast cancer provide specific considerations for male patients. (see Table 3)

Table 3. Special Considerations for Breast Cancer In Males (Sex Assigned At Birth)

Source: [National Comprehensive Cancer Network]a- See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic.BCS: breast-conserving surgery; CDK4/6: cyclin-dependent kinases 4 and 6; GnRH: gonadotropin-releasing hormone; mTOR: mammalian target of rapamycin; PARP: poly (ADP-ribose) polymerase; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; SLNB: sentinel lymph node biopsy

Decision Framework for Evaluating Breast Cancer Biomarkers

Many studies have investigated individual biomarkers or combinations of biomarkers associated with breast cancer outcomes. Determining which studies constitute sufficient evidence that the test or biomarker is likely to be clinically useful depends on attributes of the test such as its performance and the quality of the study generating the results. Simon and colleagues have described a framework to evaluate prognostic biomarker evidence.

Study designs such as prospective clinical trials or previously conducted clinical trials with archived tumor samples, constitute stronger evidence than studies with less planned and systematic patient recruitment and data collection. Randomized trials allow the determination of treatment-biomarker interactions that may be clinically important. In some clinical scenarios, demonstration of a treatment-biomarker interaction is not critical, because the decision to withhold chemotherapy in a low-risk group (to avoid chemotherapy-related morbidity) does not require the presence of a biomarker-treatment interaction. The study must generate an absolute estimate of outcomes in the patient group of interest that would result in a change in management (eg, withholding of chemotherapy), and the study must have sufficient precision (narrow confidence intervals). Results of the same test across studies should show the consistency of results and more than one study demonstrating the desired result should be available. Simon and colleagues have proposed that at least two Simon category B studies showing results consistent with clinical utility are necessary to demonstrate adequate evidence of a biomarker. Simon also proposed that while “further confirmation in a separate trial of the results gained from a category A prospective trial is always welcome, compelling results from such a trial would be considered definitive and no other validating trial would be required.”

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Oncotype DX® and other tests listed herein are available under the auspices of the CLIA. Laboratories that offer LDTs must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.

In 2007, MammaPrint (Agendia) was cleared for marketing by the FDA through the 510(k) process for the prediction of breast cancer metastasis. In 2015, MammaPrint was cleared for marketing by the FDA through the 510(k) process for use in fresh-frozen, paraffin-embedded breast cancer tissue.

In 2013, Prosigna was cleared for marketing by the FDA through the 510(k) process. The FDA determined that Prosigna was substantially equivalent to MammaPrint.

Currently, the Breast Cancer Index (Biotheranostics), EndoPredict (distributed by Myriad), Insight TNBCtype (Insight Genetics), and DCISionRT (PreludeDX) are not FDA cleared or approved.

POLICY

The use of the 21-gene reverse transcriptase-polymerase chain reaction (RT-PCR) assay (ie, Oncotype DX), EndoPredict, the Breast Cancer Index, MammaPrint, or Prosigna to determine recurrence risk for deciding whether to undergo adjuvant chemotherapy may be considered medically necessary in women with primary, invasive, node-negative breast cancer meeting all of the following characteristics:

• unilateral tumor (see Policy Guidelines);

• hormone receptor-positive (ie, ER-positive or PR-positive);

• HER2-negative;

• tumor size 0.6 to 1 cm with moderate or poor differentiation or unfavorable features OR tumor size larger than 1 cm;

• node-negative (lymph nodes with micrometastases (≤2 mm in size) are considered node-negative for this policy statement);

• who will be treated with adjuvant endocrine therapy (e.g., tamoxifen, aromatase inhibitors);

• when the test result aids the patient in deciding on chemotherapy (i.e., when chemotherapy is a therapeutic option); AND

• when ordered within 6 months after diagnosis, since the value of the test for making decisions regarding delayed chemotherapy is unknown.

The use of the MammaPrint assay to determine recurrence risk for deciding whether to undergo adjuvant chemotherapy may be considered

medically necessary

in women with primary, invasive, node positive breast cancer meeting all of the following characteristics:

• unilateral tumor;

• hormone receptor-positive (ie, ER-positive or PR-positive);

• HER2-negative;

• stage T1 or T2 or operable T3 at high clinical risk (see Policy Guidelines);

• one to three positive nodes (N1);

• no distant metastases;

• who will be treated with adjuvant endocrine therapy (eg, tamoxifen, aromatase inhibitors);

• eligible for a chemotherapy regimen containing a taxane, an anthracycline, or both;

• when the test result aids the patient in deciding on chemotherapy (ie, when chemotherapy is a therapeutic option); AND

• when ordered within 6 months after diagnosis, because the value of the test for making decisions regarding delayed chemotherapy is unknown.

The use of Oncotype Dx to determine recurrence risk for deciding whether to undergo adjuvant chemotherapy may be considered medically necessary in women with primary, invasive, node positive breast cancer meeting all of the following characteristics:

• postmenopausal (defined as previous bilateral oophorectomy or more than 12 months since the last menstrual period and no previous hysterectomy);

• unilateral tumor;

• hormone receptor-positive (ie, ER-positive or PR-positive);

• HER2-negative;

• stage T1 or T2 or operable T3 at high clinical risk (see Policy Guidelines);

• 1 to 3 positive nodes (N1);

• no distant metastases;

• who will be treated with adjuvant endocrine therapy (eg, tamoxifen, aromatase inhibitors);

• eligible for a chemotherapy regimen containing a taxane, an anthracycline, or both;

• when the test result aids the patient in deciding on chemotherapy (ie, when chemotherapy is a therapeutic option); AND

• when ordered within 6 months after diagnosis, because the value of the test for making decisions regarding delayed chemotherapy is unknown.

The use of Oncotype Dx to determine recurrence risk for deciding whether to undergo adjuvant chemotherapy in premenopausal women (defined as less than 6 months since the last menstrual period) with primary, invasive, node positive breast cancer is considered investigational (see Policy Guidelines).

The use of EndoPredict, the Breast Cancer Index, and Prosigna to determine recurrence risk for deciding whether to undergo adjuvant chemotherapy in individuals with primary, invasive, node positive breast cancer is considered investigational.

The Oncotype DX, EndoPredict, the Breast Cancer Index, MammaPrint, and Prosigna assays 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 above criteria (i.e., the test should not be ordered on a preliminary core biopsy). The test should be ordered in the context of a physician-patient discussion regarding risk preferences when the test result will aid in making decisions regarding chemotherapy.

For patients who otherwise meet the above characteristics but who have multiple ipsilateral primary tumors, a specimen from the tumor with the most aggressive histologic characteristics should be submitted for testing. It is not necessary to test each tumor; treatment is based on the most aggressive lesion (see Policy Guidelines).

All other indications for the 21-gene RT-PCR assay (i.e., Oncotype DX), EndoPredict, the Breast Cancer Index, MammaPrint, and Prosigna, including to consider the length of treatment with endocrine therapy, repeat testing with same test, or combination testing with various tests, 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 (ie, Oncotype DX® Breast DCIS Score) to inform treatment planning after excisional surgery is considered investigational.

Use of the DCISion RT assay for predicting recurrence risk in patients with noninvasive ductal carcinoma in situ to inform treatment planning after excisional surgery is considered investigational.

The use of BluePrint in conjunction with MammaPrint or alone is considered investigational.

The use of Insight TNBCtype to aid in making decisions regarding chemotherapy in women with triple-negative breast cancer is considered investigational.

The use of gene expression assays in men with breast cancer is considered investigational.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Unfavorable features that may prompt testing in tumors from 0.6 cm to 1 cm in size include the following: angiolymphatic invasion, high histologic grade, or high nuclear grade.

The 21-gene reverse transcriptase-polymerase chain reaction 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.

Current American Society of Clinical Oncology and College of American Pathologists joint guidelines on HER2 testing in breast cancer (Wolff et al [2013]) have defined positive, negative, and equivocal HER2 test results.

Unilateral Bilateral Premenopausal

Most breast cancer is unilateral, occurring in one breast. Bilateral breast cancer, breast cancer in both breasts, can be synchronous or metachronous. Synchronous is generally defined as occurring within 6 months, but other intervals are used (3 months or even 12 months), and overall, inconsistency in the use of the term “bilateral breast cancer” occurs. It is difficult to clearly know if a second breast cancer appearing within months of the first is metastatic spread or a new primary. There are no professional guidelines on use of gene expression assays in bilateral breast cancers, although small studies show Oncotype Dx score discordancy in synchronous bilateral ER-positive HER2-negative breast cancer with associated chemotherapy recommendation changes of 50% to 57%. No health outcomes were reported from the change in chemotherapy recommendations. As such, the position relates only to unilateral breast cancer although at the local level, consideration could be given to genetic expression assay in a second cancer in the contralateral breast.

Premenopausal

The position on premenopausal women with node positive breast cancer differs from the NCCN guidelines ( https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf ). The NCCN guidelines have a 2A recommendation for OncotypeDx testing of premenopausal women with 1-3 positive lymph nodes based on the RxPONDER trial. Based on this test, the NCCN guidelines have a recommendation to “consider chemotherapy followed by endocrine therapy or alternatively, ovarian function suppression combined with either tamoxifen or an Aromatase inhibitor.” Note that RxPONDER was not designed to test whether chemotherapy can be replaced by ovarian suppression, and that among premenopausal women, invasive disease–free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with a similar increase in distant relapse–free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009) indicating benefit of chemoendocrine therapy. While the evidence then is insufficient to support Oncotype DX testing as perhaps all premenopausal women benefit from chemoendocrine therapy regardless of Oncotype DX recurrence score, with the NCCN 2A recommendation for using Oncotype Dx testing for premenopausal women, a local decision might need to be made.

Clinical Risk

In the MINDACT trial (Cardoso 2016), low versus high clinical risk was determined using the Adjuvant! Online tool (version 8.0 with HER2 status, www.adjuvantonline.com ). The Adjuvant tool includes factors for age, comorbidities, ER status, tumor grade and size and number of positive nodes. In MINDACT, ER-positive, HER2-negative, node-positive patients were classified as high clinical risk if they met any of the following additional criteria:

• Grade: well differentiated; tumor size, 2.1 cm to 5 cm

• Grade: moderately differentiated; tumor size, any size

• Grade: poorly differentiated or undifferentiated; tumor size, any size.

Multiple Ipsilateral Tumors

Gene expression assay testing on multiple ipsilateral primary tumors could start with assessing the most histologically aggressive, as concordance of Oncotype Dx score with Nottingham score is strong. However, a low Oncotype Dx score indicating no need for adjuvant chemotherapy from the most aggressive appearing tumor might not negate the need for Oncotype Dx testing of other primary tumors. The literature base for this strategy is slim; but, for ipsilateral multiple tumors, Toole and colleagues show that 22% (4 out of 18) had Oncotype Dx score differences that led to changes in management. Additionally though, Toole and colleagues found that in a small number of cases, the histology and grade were the same on ipsilateral lesions, yet had significantly different Oncotype Dx scores altering chemotherapy recommendations. Larger, prospective studies are needed, including clinical outcomes from management changes. Consideration at the local level could be given to histologically distinct tumors meeting the other criteria for gene expression assay testing, or serial testing. There is no literature assessing the use of one gene expression assay on one tumor and a different gene expression assay on another ipsilateral tumor.

Unfavorable features that may prompt testing in tumors from 0.6 cm to 1 cm in size include the following: angiolymphatic invasion, high histologic grade, or high nuclear grade.

The 21-gene reverse transcriptase-polymerase chain reaction 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.

Current American Society of Clinical Oncology and College of American Pathologists joint guidelines on HER2 testing in breast cancer (Wolff et al [202 3]) have defined positive, negative, and equivocal HER2 test results.

Male Breast Cancer

For the purposes of this policy, the terms males and females are used to denote sex assigned at birth. Due to the limited participation of males in breast cancer clinical trials, the recommendations for managing breast cancer in males are predominantly based on extrapolations from data obtained from female breast cancer trials. While there are some biological and clinical differences between breast cancer in males and females, the management of breast cancer in males generally mirrors that of females, with specific considerations for male patients. According to the current NCCN guidelines on breast cancer, there is a scarcity of data on the use of molecular assays for predicting prognosis and chemotherapy benefits in male breast cancer patients. Nonetheless, the NCCN highlights that existing data indicate the 21-gene assay recurrence score (Oncotype DX) offers valuable prognostic insights for males with breast cancer.( https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf ).

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

3/31/2005: Approved by Medical Policy Advisory Committee (MPAC).

6/6/2005: Code Reference section completed.

3/15/2006: Policy reviewed, no changes.

3/21/2006: Coding updated. HCPCS 2006 revision added to policy.

1/21/2008: Oncotype DX^TM added to policy statement.

1/23/2008: CPT 89240 added to covered codes. Non-covered codes table changed to covered codes table for the Oncotype DX^TM as outlined in the POLICY section. Description section updated.

3/27/2008: Reviewed and approved by the Medical Policy Advisory Committee (MPAC).

10/7/2008: Policy statement rewritten and clarified.

04/20/2010: Policy description updated. Policy statements revised to add more detail; specific statements added regarding testing of multiple ipsilateral primaries and timing of Oncotype DX testing (i.e., within 6 months following diagnosis). Outdated references deleted from the Sources section.

08/02/2011: Policy reviewed; no changes.

03/13/2013: Policy description revised regarding available assays. The investigational policy statement for Oncotype DX was revised to include breast cancer patients with positive lymph nodes and patients with bilateral disease. Added the following policy statement: 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 investigational policy statement regarding the use of other gene expression assays for any indication was expanded to add the following tests: MammaPrint 70-gene signature, Mammostrat Breast Cancer Test, the Breast Cancer Index, the BreastOncPx, NexCourse Breast IHC4, or PAM50 Breast Cancer Intrinsic Classifier.

09/22/2014: Policy description updated regarding available assays. Added the following tests to the investigational policy statement: Prosigna™ BreastPRS™, and EndoPredict™. Added the following policy statements: 1) The use of gene expression assays in men with breast cancer is considered investigational. 2) The use of gene expression assays to molecularly subclassify breast cancer (eg, BluePrint®) is considered investigational. 3) The use of gene expression assays for quantitative assessment of ER, PR, and HER2 overexpression (eg, TargetPrint®) is considered investigational.

04/27/2015: Added CPT code 81519 to the Code Reference section.

07/06/2015: Code Reference section updated for ICD-10.

12/31/2015: Policy guidelines updated to add medically necessary and investigative definitions.

02/02/2016: Policy description updated regarding gene expression tests for breast cancer. Medically necessary policy statement updated to make the following changes: "women with breast cancer" changed to "women with primary, invasive breast cancer" and "unilateral, non-fixed tumor" changed to "unilateral tumor."

06/06/2016: Policy number A.2.04.36 added.

09/15/2017: Policy description updated regarding tests and indications for testing. Added statement that the use of EndoPredict, the Breast Cancer IndexSM, and Prosigna may be considered medically necessary for the same indications as Oncotype DX®. Revised policy statement to add EndoPredict, the Breast Cancer IndexSM, and Prosigna as investigational for all other indications, including to consider length of treatment with tamoxifen. Added the following statements: 1) Use of 70-gene signature (MammaPrint®) for any indication is considered investigational. 2) The use of BluePrint in conjunction with MammaPrint® or alone is considered investigational. Removed the following: 1) The use of other gene expression assays, MammaPrint® 70-gene signature, Mammostrat® Breast Cancer Test, the Breast Cancer IndexSM, BreastOncPx™, NexCourse® Breast IHC4, Prosigna®, BreastPRS™, and EndoPredict® for any indication is considered investigational. 2) The use of gene expression assays to molecularly subclassify breast cancer (eg, BluePrint®) is considered investigational. 3)The use of gene expression assays for quantitative assessment of ER, PR, and HER2 overexpression (eg, TargetPrint®) is considered investigational. Code Reference section updated to add CPT code 0008M.

10/13/2017: Policy description updated regarding newly diagnosed breast cancer, selection of extended endocrine therapy, and breast cancer-specific outcomes. Policy statements unchanged.

12/21/2017: Code Reference section updated to add new 2018 CPT code 81520 as covered and 81521 as investigational.

01/08/2018: Policy description updated regarding gene expression tests. Policy statements unchanged.

06/29/2018: Code Reference section updated to add new CPT code 0045U, effective 07/01/2018.

07/27/2018: Policy reviewed; no changes.

10/01/2018: Code Reference section updated to add new CPT code 0067U.

12/18/2018: Code Reference section updated to add new CPT code 81518, effective 01/01/2019.

01/15/2019: Policy description updated regarding guidelines for extended endocrine therapy. Policy statement revised to add MammaPrint to the list of tests considered medically necessary. Policy statement updated to add that all other indications for MammaPrint are considered investigational. Removed the following statement: Use of 70-gene signature (MammaPrint) for any indication is considered investigational. Code Reference section updated to move CPT code 81521 from investigational to covered. Added CPT code 0009U to investigational codes table. Removed deleted CPT code 0008M.

07/15/2019: Policy description updated regarding the American Society for Clinical Oncology guidelines and the outcomes of studies regarding extended endocrine therapy. Policy statements unchanged.

12/19/2019: Code Reference section updated to add new CPT codes 81522 and 0153U effective 01/01/2020.

06/23/2020: Policy description updated. Second medically necessary statement updated to remove MammaPrint. Added separate medically necessary statement for MammaPrint for node-positive (1 to 3 nodes) women making decisions regarding adjuvant chemotherapy. Policy Guidelines updated regarding determination of low versus high clinical risk.

09/23/2020: Code Reference section updated to add new CPT code 0220U, effective 10/01/2020.

09/01/2021: Policy description updated to add information regarding the decision to pursue neoadjuvant chemotherapy in women with Triple-Negative Breast Cancer (TNBC). Added policy statement that the use of Insight TNBCtype to aid in making decisions regarding chemotherapy in women with triple-negative breast cancer is considered investigational. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and to change "Medically Necessary" to "medical necessity."

12/15/2021: Code Reference section updated to add new CPT codes 81523 and 0295U, effective 01/01/2022.

07/26/2022: Policy description updated regarding randomized trials evaluating adjuvant extended endocrine therapies for hormone receptor-positive breast cancer. First investigational policy statement updated to change "tamoxifen" to "endocrine therapy." Policy Guidelines updated.

03/09/2023: Policy description updated regarding newly diagnosed breast cancer and tests. First medically necessary statement updated to include EndoPredict, the Breast Cancer Index, MammaPrint, Prosigna, and node negative breast cancer. Medically necessary statement regarding the MammaPrint assay updated to include node positive breast cancer and to add the following criteria: 1) no distant metastases; 2) eligible for a chemotherapy regimen containing a taxane, an anthracycline, or both. Added medically necessary statement regarding the use of the Oncotype Dx in women with primary, invasive, node positive breast cancer. Added investigational statements for the following: 1) The use of Oncotype Dx in premenopausal women with primary, invasive, node positive breast cancer; 2) The use of EndoPredict, the Breast Cancer Index, and Prosigna in individuals with primary, invasive, node positive breast cancer; and 3) The use of the DCISion RT assay in patients with noninvasive ductal carcinoma in situ. Revised investigational statement regarding all other indications for the 21-gene RT-PCR assay, EndoPredict, the Breast Cancer Index, MammaPrint, and Prosigna to include repeat and combination testing. Policy Guidelines updated regarding unilateral breast cancer, bilateral breast cancer, premenopausal women, and multiple ipsilateral tumors.

12/19/2023: Policy description updated regarding newly diagnosed breast cancer and randomized trials. Policy statements unchanged. Policy Guidelines updated regarding testing.

02/05/2025: Policy description updated regarding newly diagnosed breast cancer and breast cancer in males. Policy statements unchanged. Policy Guidelines updated regarding male breast cancer.

07/18/2025: Code Reference section updated to add new CPT code 0559U. Effective 07/01/2025.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.36

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

Investigational Codes

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