Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2022040
Category:	Laboratory
Initiated:	February 2023
Last Review:	January 2024

Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Breast Cancer

Description:

Multiple biomarkers are being evaluated to predict response to targeted treatments and immunotherapy for patients with advanced or high-risk breast cancer. These include tissue-based testing as well as circulating tumor DNA and circulating tumor cell testing (known as liquid biopsy).

The objective of this evidence review is to examine whether biomarker testing for BRCA variants, PIK3CA, NTRK gene fusions, PD-L1, MSI-H/dMMR, Ki-67, TMB, circulating tumor DNA, or circulating tumor cells improves the net health outcome in patients with breast cancer who are considering targeted therapy or immunotherapy.

BRCA Variant Testing

The prevalence of BRCA variants is approximately 0.1% to 0.2% in the general population (Nelson, 2019). The prevalence may be much higher for particular ethnic groups with characterized founder mutations (e.g., 2.5% [1/40] in the Ashkenazi Jewish population). Family history of breast and ovarian cancer is an important risk factor for the BRCA variant; additionally, age and ethnicity could be independent risk factors.

Several genetic syndromes with an autosomal dominant pattern of inheritance that features breast cancer have been identified (Hemel, 2010). Of these, hereditary breast and ovarian cancer (HBOC) and some cases of hereditary site-specific breast cancer have in common causative variants in BRCA (breast cancer susceptibility) genes. Families suspected of having HBOC syndrome are characterized by an increased susceptibility to breast cancer occurring at a young age, bilateral breast cancer, male breast cancer, ovarian cancer at any age, as well as cancer of the fallopian tube and primary peritoneal cancer. Other cancers, such as prostate cancer, pancreatic cancer, gastrointestinal cancers, melanoma, and laryngeal cancer, occur more frequently in HBOC families. Hereditary site-specific breast cancer families are characterized by early-onset breast cancer with or without male cases, but without ovarian cancer. For this evidence review, BCBSA refers collectively to both as hereditary breast and/or ovarian cancer.

Germline variants in the BRCA1 and BRCA2 genes are responsible for the cancer susceptibility in most HBOC families, especially if ovarian cancer or male breast cancer are features (Yoshida, 2021). However, in site-specific cancer, BRCA variants are responsible only for a proportion of affected families. BRCA gene variants are inherited in an autosomal dominant fashion through maternal or paternal lineage. It is possible to test for abnormalities in BRCA1 and BRCA2 genes to identify the specific variant in cancer cases and to identify family members at increased cancer risk. Family members without existing cancer who are found to have BRCA variants can consider preventive interventions for reducing risk and mortality.

Young age of onset of breast cancer, even in the absence of family history, is a risk factor for BRCA1 variants. Winchester estimated that hereditary breast cancers account for 36% to 85% of patients diagnosed before age 30 (Winchester, 1996). In several studies, BRCA variants were independently predicted by early age at onset, being present in 6% to 10% of breast cancer cases diagnosed at ages younger than various premenopausal age cutoffs (age range, 35-50 years) (Winchester, 1996; Frank, 2002; Langston, 1996; Malone, 1998). In cancer-prone families, the mean age of breast cancer diagnosis among women carrying BRCA1 or BRCA2 variants is in the 40s (Ford, 1998). In the Ashkenazi Jewish population, Frank et al reported that 13% of 248 cases with no known family history and diagnosed before 50 years of age had BRCA variants (Frank, 2002). In a similar study by Gershoni-Baruch et al, 31% of Ashkenazi Jewish women, unselected for family history, diagnosed with breast cancer at younger than 42 years of age had BRCA variants (Gershoni-Baruch, 2000). Other studies have indicated that early age of breast cancer diagnosis is a significant predictor of BRCA variants in the absence of family history in this population (Warner, 1999; Hartge, 1999; Hodgson, 1999).

In patients with “triple-negative” breast cancer (i.e., negative for expression of estrogen, progesterone, and overexpression of human epidermal growth factor receptor 2 [HER2] receptors), there is an increased prevalence of BRCA variants. Pathophysiologic research has suggested that the physiologic pathway for the development of triple-negative breast cancer is similar to that for BRCA-associated breast cancer (de Ruijter, 2011). Young et al studied 54 women with high-grade, triple-negative breast cancer with no family history of breast or ovarian cancer, representing a group that previously was not recommended for BRCA testing (Young, 2009). Six BRCA variants (5 BRCA1, 1 BRCA2) were found, for a variant rate of 11%. Finally, Gonzalez-Angulo et al in a study of 77 patients with triple-negative breast cancer, reported that 15 patients (19.5%) had BRCA variants (12 in BRCA1, 3 in BRCA2) (Gonzalez-Angulo, 2011).

PIK3CA Testing

Alterations in the protein coding gene PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha) occur in approximately 40% of patients with hormone receptor (HR)-positive, HER2-negative breast cancer (Karakas, 2006).

NTRK Gene Fusions

Neurotrophic-tropomyosin receptor kinase (NTRK) gene fusions encode tropomyosin receptor kinase fusion proteins that act as oncogenic drivers for solid tumors including lung, salivary gland, thyroid, and sarcoma. NTRK gene fusion findings might be more highly associated with rare breast cancer subtypes (e.g., secretory carcinoma) (NCCN, 2022).

Programmed Cell Death Ligand Protein-1

Programmed cell death ligand-1 (PD-L1) is a transmembrane protein expressed on the surface of multiple tissue types, including many tumor cells. Blocking the PD-L1 protein may prevent cancer cells from inactivating T cells.

Mismatch Repair Deficiency/Microsatellite Instability

Mismatch repair deficiency (dMMR) and high levels of microsatellite instability (MSI-H) describe cells that have alterations in certain genes involved in correcting errors made when DNA is replicated. dMMR tumors are characterized by a high tumor mutational load and potential responsiveness to anti-PD-L1-immunotherapy. MMR deficiency is most common in colorectal cancer, other types of gastrointestinal cancer, and endometrial cancer, but it may also be found in other cancers including breast cancer. Microsatellite instability testing is generally performed using polymerase chain reaction (PCR) for 5 biomarkers, although other biomarker panels and next generation sequencing are sometimes performed. High microsatellite instability is defined as 2 or more of the 5 biomarkers showing instability or more than 30% of the tested biomarkers showing instability depending on what panel is used. Microsatellite instability testing is generally paired with immunohistochemistry (IHC) assessing lack of protein expression from 4 DNA mismatch repair genes thereby reflecting dMMR (Bonneville, 2020).

Ki-67

Ki-67 is a nuclear protein used to detect and quantify the rate of tumor cell proliferation and has been investigated as a prognostic biomarker for breast cancer (Davey, 2021).

Tumor Mutational Burden

Tumor mutational burden (TMB), a measure of gene mutations within cancer cells, is an emerging biomarker of outcomes with immunotherapy in multiple tumor types. Initially, assessments of TMB involved whole exome sequencing (WES). More recently, targeted next generation sequencing (NGS) panels are being adapted to estimate TMB. Currently FoundationOne CDx is the only U.S. Food and Drug Administration (FDA) approved panel for estimating TMB, but others are in development (Merino, 2020).

Rearranged During Transfection

The REarranged during Transfection (RET) proto-oncogene encodes a receptor tyrosine kinase growth factor (Regua, 2022). Translocations that result in fusion genes with several partners have been reported and occur in about 5-10% of thyroid cancer cases (primarily papillary thyroid carcinoma) and 1%-2% of non-small-cell lung cancer cases. RET fusions in breast cancer, occur in less than 1% of cases (Santoro, 2020).

BRAF

RAF proteins are serine/threonine kinases that are downstream of RAS in the RAS-RAF-ERK-MAPK pathway. The most common mutation locus is found in codon 600 of exon 15 (V600E) of the BRAF gene, causing constitutive hyperactivation, proliferation, differentiation, survival, and oncogenic transformation (Wang, 2022). BRAF mutations occur in approximately 1% of breast cancer cases (Albanell, 2016).

ESR1

Mutations in ESR1, which occur in approximately 10-20% of patients with metastatic estrogen receptor-positive breast cancer, confer resistance to endocrine therapy via constitutive activation of estrogen receptor-mediated growth activity (Toy, 2013; Jeselsohn, 2014).

Circulating Tumor DNA

Normal and tumor cells release small fragments of DNA into the blood, which is referred to as cell-free DNA. Cell-free DNA from nonmalignant cells is released by apoptosis. Most cell-free tumor DNA is derived from apoptotic and/or necrotic tumor cells, either from the primary tumor, metastases, or CTCs. Unlike apoptosis, necrosis is considered a pathologic process and generates larger DNA fragments due to incomplete and random digestion of genomic DNA. The length or integrity of the circulating DNA can potentially distinguish between apoptotic and necrotic origin. Circulating tumor DNA can be used for genomic characterization of the tumor.

Circulating Tumor Cells

Intact circulating tumor cells (CTCs) are released from a primary tumor and/or a metastatic site into the bloodstream. The half-life of a CTC in the bloodstream is short (1-2 hours), and CTCs are cleared through extravasation into secondary organs. Most assays detect CTCs through the use of surface epithelial markers such as EpCAM and cytokeratins. The primary reason for in detecting CTCs is prognostic, through quantification of circulating levels.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.

An up-to-date list of FDA cleared or approved companion diagnostics is available at https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools.

Policy/
Coverage:

Effective February 2024

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Genetic testing for BRCA1 or BRCA2 germline variants meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to PARP inhibitors (e.g., olaparib [Lynparza] and talazoparib [Talzenna]) for human epidermal receptor 2 (HER2)-negative metastatic and early stage, high-risk breast cancer.

PIK3CA testing meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to alpelisib (e.g., Piqray) in individuals with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer who have progressed on or after an endocrine-based regimen.

When tumor tissue is available, use of tissue for testing is preferred but is not required (see Circulating Tumor DNA Testing below).

Analysis of NTRK gene fusions meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to entrectinib (e.g., Rozlytrek) or larotrectinib (e.g., Vitrakvi) in individuals with locally advanced or metastatic breast cancer that has progressed following standard treatment and who have no alternative treatment option.

PD-L1 testing meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to pembrolizumab (e.g., Keytruda) in individuals with hormone receptor-negative/HER2-negative (triple negative) recurrent or metastatic breast cancer.

MSI-H/dMMR testing meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to pembrolizumab (e.g., Keytruda) in individuals with unresectable or metastatic breast cancer that has progressed following standard treatment and who have no alternative treatment option.

PIK3CA testing using FoundationOne Liquid CDx meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to alpelisib (e.g., Piqray) in individuals with hormone receptor-positive, HER2 negative advanced or metastatic breast cancer who have progressed on or after an endocrine-based regimen.

When tumor tissue is available, use of tissue for testing is preferred but is not required.

ESR1 testing using Guardant360 CDx meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to elacestrant (Orserdu) in individuals with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Genetic testing of BRCA1 or BRCA2 germline or somatic variants in individuals with breast cancer for guiding therapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other situations not addressed in this or any other policy.

For members with contracts without primary coverage criteria, genetic testing of BRCA1 or BRCA2 germline or somatic variants in individuals with breast cancer for guiding therapy is considered investigational in all other situations not addressed in this or any other policy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

PIK3CA testing of tissue in individuals with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other situations not addressed in this or any other policy.

For members with contracts without primary coverage criteria, PIK3CA testing of tissue in individuals with breast cancer is considered investigational in all other situations not addressed in this or any other policy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Analysis of NTRK gene fusions in individuals with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other situations not addressed in this or any other policy.

For members with contracts without primary coverage criteria, analysis of NTRK gene fusions in individuals with breast cancer is considered investigational in all other situations not addressed in this or any other policy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

PD-L1 testing in individuals with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other situations not addressed in this or any other policy, including to predict treatment response to atezolizumab (e.g., Tecentriq).

For members with contracts without primary coverage criteria, PD-L1 testing in individuals with breast cancer is considered investigational all other situations not addressed in this or any other policy, including to predict treatment response to atezolizumab (e.g., Tecentriq). Investigational services are specific contract exclusions in most member benefit certificates of coverage.

MSI-H/dMMR testing in individuals with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other situations not addressed in this or any other policy, including to predict treatment response to dostarlimab-gxly (e.g., Jemperli).

For members with contracts without primary coverage criteria, MSI-H/dMMR testing in individuals with breast cancer is considered investigational in all other situations not addressed in this or any other policy, including to predict treatment response to dostarlimab-gxly (e.g., Jemperli). Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Ki-67 testing to predict treatment response to abemaciclib (e.g., Verzenio) in individuals with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For members with contracts without primary coverage criteria, Ki-67 testing to predict treatment response to abemaciclib (e.g., Verzenio) in individuals with breast cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Tumor mutational burden testing to predict response to immunotherapy in individuals with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For members with contracts without primary coverage criteria, tumor mutational burden testing to predict response to immunotherapy in individuals with breast cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Circulating tumor DNA testing in individuals with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other situations not addressed in this or any other policy.

For members with contracts without primary coverage criteria, circulating tumor DNA testing in individuals with breast cancer is considered investigational in all other situations not addressed in this or any other policy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Analysis of circulating tumor cells to select treatment in individuals with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For members with contracts without primary coverage criteria, analysis of circulating tumor cells to select treatment in individuals with breast cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

RET testing to predict treatment response to selpercatinib (Retevmo) in individuals with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For members with contracts without primary coverage criteria, RET testing to predict treatment response to selpercatinib (Retevmo) in individuals with breast cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

BRAF testing to predict treatment response to dabrafenib (Tafinlar) plus trametinib (Mekinist) in individuals with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For members with contracts without primary coverage criteria, BRAF testing to predict treatment response to dabrafenib (Tafinlar) plus trametinib (Mekinist) in individuals with breast cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

ESR1 testing using Guardant360 CDx does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other situations not addressed in this or any other policy.

For members with contracts without primary coverage criteria, ESR1 testing using Guardant360 CDx is considered investigational in all other situations not addressed in this or any other policy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective June 15, 2023 through January 2024

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

When tumor tissue is available, use of tissue for testing is preferred but is not required (see Circulating Tumor DNA Testing below).

When tumor tissue is available, use of tissue for testing is preferred but is not required.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

For members with contracts without primary coverage criteria, genetic testing of BRCA1 or BRCA2 germline or somatic variants in individuals with breast cancer for guiding therapy is considered investigational in all other situations not addressed in this or any other policy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

For members with contracts without primary coverage criteria, analysis of NTRK gene fusions in individuals with breast cancer is considered investigational in all other situations not addressed in this or any other policy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

For members with contracts without primary coverage criteria, PD-L1 testing in individuals with breast cancer is considered investigational all other situations not addressed in this or any other policy, including to predict treatment response to atezolizumab (e.g., Tecentriq). Investigational services are specific contract exclusions in most member benefit certificates of coverage.

For members with contracts without primary coverage criteria, MSI-H/dMMR testing in individuals with breast cancer is considered investigational in all other situations not addressed in this or any other policy, including to predict treatment response to dostarlimab-gxly (e.g., Jemperli). Investigational services are specific contract exclusions in most member benefit certificates of coverage.

For members with contracts without primary coverage criteria, Ki-67 testing to predict treatment response to abemaciclib (e.g., Verzenio) in individuals with breast cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

For members with contracts without primary coverage criteria, tumor mutational burden testing to predict response to immunotherapy in individuals with breast cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

For members with contracts without primary coverage criteria, circulating tumor DNA testing in individuals with breast cancer is considered investigational in all other situations not addressed in this or any other policy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

For members with contracts without primary coverage criteria, analysis of circulating tumor cells to select treatment in individuals with breast cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

For members with contracts without primary coverage criteria, RET testing to predict treatment response to selpercatinib (Retevmo) in individuals with breast cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective February 15, 2023 through June 14, 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Genetic testing for BRCA1 or BRCA2 germline variants meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to PARP inhibitors (e.g., olaparib [Lynparza] and talazoparib [Talzenna]) for human epidermal receptor 2 (HER2)-negative metastatic and early stage, high-risk breast cancer.

PIK3CA testing meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to alpelisib (e.g., Piqray) in patients with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer who have progressed on or after an endocrine-based regimen.

When tumor tissue is available, use of tissue for testing is preferred but is not required (see Circulating Tumor DNA Testing below).

Analysis of NTRK gene fusions meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to entrectinib (e.g., Rozlytrek) or larotrectinib (e.g., Vitrakvi) in patients with locally advanced or metastatic breast cancer that has progressed following standard treatment and who have no alternative treatment option.

PD-L1 testing meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to pembrolizumab (e.g., Keytruda) in patients with hormone receptor-negative/HER2-negative (triple negative) recurrent or metastatic breast cancer.

MSI-H/dMMR testing meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to pembrolizumab (e.g., Keytruda) in patients with unresectable or metastatic breast cancer that has progressed following standard treatment and who have no alternative treatment option.

PIK3CA testing using FoundationOne Liquid CDx meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness to predict treatment response to alpelisib (e.g., Piqray) in patients with hormone receptor-positive, HER2 negative advanced or metastatic breast cancer who have progressed on or after an endocrine-based regimen.

When tumor tissue is available, use of tissue for testing is preferred but is not required.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Genetic testing of BRCA1 or BRCA2 germline or somatic variants in patients with breast cancer for guiding therapy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other situations not addressed in this or any other policy.

For members with contracts without primary coverage criteria, genetic testing of BRCA1 or BRCA2 germline or somatic variants in patients with breast cancer for guiding therapy is considered investigational in all other situations not addressed in this or any other policy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

PIK3CA testing of tissue in patients with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other situations not addressed in this or any other policy.

For members with contracts without primary coverage criteria, PIK3CA testing of tissue in patients with breast cancer is considered investigational in all other situations not addressed in this or any other policy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Analysis of NTRK gene fusions in patients with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other situations not addressed in this or any other policy.

For members with contracts without primary coverage criteria, analysis of NTRK gene fusions in patients with breast cancer is considered investigational in all other situations not addressed in this or any other policy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

PD-L1 testing in patients with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other situations not addressed in this or any other policy, including to predict treatment response to atezolizumab (e.g., Tecentriq).

For members with contracts without primary coverage criteria, PD-L1 testing in patients with breast cancer is considered investigational all other situations not addressed in this or any other policy, including to predict treatment response to atezolizumab (e.g., Tecentriq). Investigational services are specific contract exclusions in most member benefit certificates of coverage.

MSI-H/dMMR testing in patients with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other situations not addressed in this or any other policy, including to predict treatment response to dostarlimab-gxly (e.g., Jemperli).

For members with contracts without primary coverage criteria, MSI-H/dMMR testing in patients with breast cancer is considered investigational in all other situations not addressed in this or any other policy, including to predict treatment response to dostarlimab-gxly (e.g., Jemperli). Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Ki-67 testing to predict treatment response to abemaciclib (e.g., Verzenio) in patients with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For members with contracts without primary coverage criteria, Ki-67 testing to predict treatment response to abemaciclib (e.g., Verzenio) in patients with breast cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Tumor mutational burden testing to predict response to immunotherapy in patients with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For members with contracts without primary coverage criteria, tumor mutational burden testing to predict response to immunotherapy in patients with breast cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Circulating tumor DNA testing in patients with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other situations not addressed in this or any other policy.

For members with contracts without primary coverage criteria, circulating tumor DNA testing in patients with breast cancer is considered investigational in all other situations not addressed in this or any other policy. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Analysis of circulating tumor cells to select treatment in patients with breast cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For members with contracts without primary coverage criteria, analysis of circulating tumor cells to select treatment in patients with breast cancer is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

“Due to the detail of the rationale, the complete document is not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com”

This evidence review was created in December 2020 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through November 8, 2021.

Breast cancer treatment selection is informed by tumor type, grade, stage, patient performance status and preference, prior treatments, and the molecular characteristics of the tumor such as the presence of driver mutations. One purpose of biomarker testing of patients who have advanced cancer is to inform a decision regarding treatment selection (e.g., whether to select a targeted treatment or standard treatment).

BRCA Variants

BRACAnalysis CDx is an FDA-approved companion diagnostic test for olaparib and talazoparib.

Numerous clinical trials have been conducted to evaluate the effectiveness of PARP inhibitors in individuals with hereditary breast and ovarian cancer (HBOC) Syndrome or other high-risk cancers confirmed to have a BRCA1/2 mutation. Summarized below are the pivotal trials that supported the BRCA mutation-related FDA approved indications.

Tutt et al published results from the phase 3 multicenter, multinational, and double-blind OlympiA RCT, which evaluated the safety and efficacy of olaparib in patients with germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants and high-risk, human epidermal growth factor receptor 2 (HER2)-negative primary early-stage breast cancer after definitive local treatment and neoadjuvant or adjuvant chemotherapy (Tutt, 2021). Patients with triple-negative breast cancer who were treated with adjuvant chemotherapy were required to have axillary node-positive disease or an invasive primary tumor measuring at least 2 cm on pathological analysis. Patients treated with neoadjuvant chemotherapy were required to have not achieved pathological complete response. Patients treated with adjuvant chemotherapy for hormone receptor (HR)-positive, HER2-negative breast cancer were required to have at least 4 pathologically confirmed positive lymph nodes. Those treated with neoadjuvant chemotherapy were required to have not achieved a pathological complete response with a CPS+EG score of 3 or higher. This scoring system estimates relapse probability on the basis of clinical and pathological stage (CPS) and estrogen-receptor status and histologic grade (EG). Scores range from 0 to 6, with higher scores reflecting a worse prognosis. Approximately half of patients received adjuvant chemotherapy and half neoadjuvant chemotherapy, with the majority (93.7%) receiving a combination of an anthracycline and a taxane in their regimen. Patients with triple-negative disease comprised 82.2% of the trial population. Patients were randomized 1:1 to treatment with twice daily 300 mg olaparib (n = 921) or placebo (n=915) for 52 weeks. At the prespecified interim analysis, 86% of the primary analysis target of 330 events of invasive disease or death in the intention-to-treat population were observed, with a median follow-up duration of 2.5 years (interquartile range [IQR], 1.5 to 3.5 y). The 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8%; 95% CI, 4.5% to 13.0%). Invasive disease-free survival was significantly longer among patients receiving olaparib (hazard ratio [HR], 0.58; 99.5% CI, 0.41 to 0.82; p<.001). Distant disease-free survival at 3 years was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1%; 95% CI, 3.0% to 11.1%). This outcome was significantly longer among patients assigned to receive olaparib (HR, 0.57; 99.5% CI, 0.39 to 0.83; p<.001). While fewer deaths were reported in the olaparib group (59 versus 86) with a HR of 0.68 (99% CI, 0.44 to 1.05; p=.02), the between-group difference did not cross the prespecified multiple-testing procedure boundary for significance of p<.01. Subgroup analysis of invasive disease-free survival revealed treatment effects for olaparib over placebo that were consistent with those in the overall analysis population across all stratification groups and prespecified subgroups. Serious adverse events occurred in 8.7% and 8.4% of patients treated with olaparib and placebo, respectively. Adverse events leading to trial regimen discontinuation occurred in 9.9% and 4.2% of patients treated with olaparib and placebo, respectively.

OlympiAD is a phase 3 RCT in which patients with HER2-negative metastatic breast cancer and a germline BRCA variant were randomized to olaparib (n=205) or standard therapy (n=97) (Robson, 2017). BRCA1/2 mutation was detected by BRACAnalysis testing. In its initial publication, Robson et al (2017) reported that after a median follow-up of 14.5 months, patients receiving olaparib experienced significantly longer progression-free survival (PFS) compared with patients receiving standard therapy (HR, 0.6; 95% CI, 0.4 to 0.8) (Robson, 2017). The rate of grade 3 or higher adverse events was lower in the group receiving olaparib (37%) compared with the group receiving standard therapy (51%). However, regarding overall survival, in their subsequent publication, Robson et al further reported that although improvement with olaparib was not significant overall (19.3 vs 17.1 months; HR, 0.90; 95% CI, 0.66 to 1.23) there may be a benefit in the subgroup of patients who had not received chemotherapy for metastatic disease (HR, 0.51; 95% CI, 0.29-0.90) (Robson, 2019).

Litton et al published results from a phase 3, randomized, open-label trial of 431 patients with advanced breast cancer and a germline BRCA1/2 mutation that compared talazoparib 1 mg once daily to standard single-agent therapy (EMBRACA) (Litton, 2018). BRCA1/2 mutation was detected by BRACAnalysis testing. The primary endpoint was PFS. Median duration of follow-up for that endpoint was 11.2 months. Progression-free survival was significantly longer in the talazoparib group (8.6 months vs 5.6 months; HR 0.54, 95% CI, 0.41 to 0.71). The rate of overall grade 3 or higher adverse events was similar for talazoparib compared with the standard care (25.5% vs 25.4%), but hematologic grade 3-4 adverse events (primarily anemia) were more frequent for talazoparib (55% vs 38%) compared with nonhematologic grade 3-4 adverse events (32% vs 38%). Based on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), compared to baseline, there was a significant improvement in the talazoparib group (+3.0; 95% CI, 1.2 to 4.8) and a significant decline in the standard therapy group (-5.4; 95% CI, -8.8 to -2.0). Although the trial was open-label, assessment of the primary outcome was based on blinded independent central review.

No studies were identified that have directly compared health outcomes in patients with breast cancer who did and did not use BRCA1 and BRCA2 variant testing to guide systemic treatment decisions. Evidence for the use of testing for BRCA1 and BRCA2 variants in individuals with breast cancer consists of several placebo-controlled RCTs of PARP inhibitor drugs that have consistently demonstrated that, in individuals identified by genetic testing as having a BRCA1 or BRCA2 variant, treatment with PARP inhibitor drugs significantly improve PFS time. In individuals with a BRCA1/2 mutation and either HER2-negative metastatic breast cancer or other advanced breast cancer who were followed for 11-12 months, treatment with a PARP inhibitor drug resulted in a 40% to 46% lower risk of disease progression or death. In individuals with a BRCA1/2 mutation and early-stage breast cancer at high-risk for recurrence, treatment with olaparib resulted in a 9% improvement in 3-year invasive disease-free survival.

PIK3CA

U.S. Food and Drug Administration (FDA) approved companion diagnostic tests for alpelisib in patients with PIK3CA-mutated breast cancer include both tissue-based and liquid biopsy assays. These tests are approved to measure 11 variants in the PIK3CA gene.

Andre et al reported results of SOLAR-1 (Clinical Studies of Alpelisib in Breast Cancer 1), a phase 3 trial to evaluate alpelisib plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously (Andre, 2019). Patients were enrolled into 2 cohorts based on tumor-mutation status (PIK3CA-mutated vs not PIK3CA-mutated) and randomly assigned within cohorts to receive oral alpelisib plus fulvestrant or placebo plus fulvestrant. PIK3CA status was determined with the use of a tumor-tissue sample, and patients had to have adequate tumor tissue for central analysis of PIK3CA mutational status. The primary end point was progression-free survival in the cohort of patients with PIK3CA-mutated cancer.

Among patients with PIK3CA-positive tumors who received targeted therapy, PFS was 11.0 months (95% CI, 7.5 to 14.5), compared to 5.7 months (95% CI, 3.7 to 7.4) in PIK3CA-positive patients who received standard care (HR 0.65; 95% CI, 0.50 to 0.85). In contrast, the HR for PFS in the cohort without PIK3CA-mutated cancer was not significantly different for the active vs placebo groups.

In a randomized, placebo-controlled trial of alpelisib compared to placebo in men and postmenopausal women with advanced breast cancer who had previously received endocrine therapy, PFS was longer among patients with PIK3CA-positive tumors who received targeted therapy, PFS was 11.0 months (95% CI, 7.5 to 14.5), compared to 5.7 months (95% CI, 3.7 to 7.4) in PIK3CA-positive patients who received standard care. In contrast, the hazard ratio for PFS in the cohort without PIK3CA-mutated cancer was not significantly different for the active vs placebo groups. The overall response rate was higher in patients with PIK3CA-positive tumors compared to the rate in the standard care group (26.6% [95% CI [20.1 to 34.0] vs 12.8% [8.2-18.7%]), with an acceptable side effect profile.

NTRK Gene Fusions

There is currently no FDA approved companion diagnostic test for entrectinib. FoundationOne CDX is an approved companion diagnostic test for larotrectinib.

Doebele et al reported an analysis of data from 3 Phase 1-2 trials of entrectinib in patients with NTRK-fusion solid tumors (Doebele, 2020). Of 54 patients included in the analysis, 6 had breast cancer (11%). Patients were assessed for eligibility for the 3 trials using either local molecular profiling or central RNA-based next-generation sequencing to test for the presence of NTRK fusions. The primary endpoints were objective response and duration of response. PFS and overall survival were secondary endpoints.

Of the total cohort of 54 patients, 31 had an objective response (57%; 95% CI, 43.2–70.8). Four patients (7%) had a complete response and 27 a partial response (50%). Responses were recorded in all tumor types, including 5 (83%; 36–100) of 6 patients with breast cancer. Median PFS for the full cohort was 11 months (95% CI, 8.0–1) and median overall survival was 21 months (95% CI, 14.9 to not estimable). There were 7 serious treatment-related adverse events (10%), and 3 (4%) patients discontinued due to a treatment-related adverse event.

Hong et al reported an analysis of 3 phase 1-2 trials of larotrectinib in patients with NTRK-fusion positive solid tumors in adults and children (Hong, 2020).

NTRK fusions were identified by next-generation sequencing, according to the procedures and analytic pipelines established by each laboratory, or by fluorescence in situ hybridization.

The trials included adults and children with 17 different solid tumors. Five patients had breast cancer (3%).

These results were consistent with a preliminary analysis of data from these trials reported by Drilon et al in 2018 (Drilon, 2018).

In an analysis of 159 patients with NTRK-fusion positive solid tumors who received larotrectinib, including 5 patients with breast tumors, the overall response rate was 79% (95% CI, 72-85). The median PFS was 28.3 months (95% CI, 22.1 to not estimable), and 67% of patients were progression-free at 12 months (95% CI, 58–76). In an integrated analysis of 3 phase 1-2 trials in 54 patients with NTRK-positive solid tumors who received entrectinib, 6 of whom had breast cancer, the overall response rate was 57% (95% CI, 43.2–70.8). At data cutoff, 16 (30%) of 54 patients had died, and the estimated median overall survival was 21 months (95% CI, 14.9 to not estimable). Responses were observed regardless of tumor type or age of the patient.

PD-L1 Testing

PD-L1 IHC 22C3 pharmDx is an approved companion diagnostic test to select patients with triple negative breast cancer for treatment with pembrolizumab.

Schmid et al reported results of a randomized, placebo-controlled trial of atezolizumab in combination with nab-paclitaxel for patients with metastatic or unresectable triple-negative breast cancer and PD-L1-positive tumors (defined as expression on >1% of tumor-infiltrating immune cells) (Schmid, 2018). PFS was longer in the group of PD-L1-positive patients who received targeted treatment, compared to those who received placebo. However, the designated confirmatory trial, IMpassion131, did not demonstrate a statistically significant improvement in investigator-assessed PFS for atezolizumab plus paclitaxel compared with placebo plus paclitaxel in the PD-L1-positive population, with a median PFS of 5.95 and 5.72 months (HR, 0.82; 95% CI, 0.60 to 1.12), respectively (FDA, 2021). In August 2021, Genentech voluntarily withdrew accelerated approval of atezolizumab (Tecentriq) for use in patients with PD-L1 positive, triple-negative breast cancer following FDA assessment of these findings.

The efficacy of pembrolizumab plus chemotherapy compared to placebo plus chemotherapy for previously untreated, locally recurrent inoperable or metastatic triple-negative breast cancer (n=847) was evaluated in the KEYNOTE-355 study conducted by Cortes and coworkers (Cortes, 2020). Dual primary efficacy endpoints were PFS and overall survival in patients with PD-L1 combined positive score ≥1. This study formed the basis of pembrolizumab accelerated approval in patients with unresectable or metastatic triple-negative breast cancer and PD-L1 CPS ≥10.

Two nonrandomized, single-arm trials reported outcomes in a total of 111 patients with PD-L1 positive triple negative breast cancer treated with pembrolizumab (Adams, 2019; Nanda, 2016).

In a placebo controlled trial of atezolizumab in combination with nab-paclitaxel for patients with PD-L1 positive triple negative breast cancer , median PFS (HR 0.62; 95% CI, 0.49 to 0.78) and overall survival 0.62 (95% CI, 0.45–0.86) were longer among patients who received the targeted immunotherapy. However, a designated confirmatory trial did not confirm these results and accelerated approval was withdrawn. In 2 nonrandomized trials of pembrolizumab for patients with PD-L1 positive triple negative breast cancer, the objective response rate was 21.4% (95% CI, 13.9 to 31.4) and 18.5% (95% CI, 6.3 to 38.1). In 1 randomized trial of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for patients with triple negative breast cancer and PD-L1 combined positive score ≥10, the median PFS was 9.7 and 5.6 months, respectively (HR, 0.65; 95% CI, 0.49 to 0.86).

MSI-H/dMMR Testing

The Ventana MMR RxDx Panel is an FDA-approved test for the detection of dMMR to guide the use of dostarlimab-gxly (Jemperli) in solid tumors. There is no FDA approved test for the detection of MSI-H or dMMR for pembrolizumab (Keytruda). In clinical trials, the identification of MSI-H or dMMR tumor status for the majority of patients (135/149) was prospectively determined using local laboratory-developed, polymerase chain reaction (PCR) tests for MSI-H status or immunohistochemistry (IHC) tests for dMMR.

Marabelle et al reported results of a phase 2 trial of pembrolizumab in 233 previously treated patients with MSI-H solid tumors, 5 of whom had breast cancer (Marabelle, 2020). The overall response rate, the primary outcome, was 34.3% (95% CI, 28.3% to 40.8%). Median PFS was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Earlier, Le et al reported on a small (N = 41) phase 2 trial that compared response to pembrolizumab in patients with solid tumors that did or did not have mismatch repair (Le, 2015). Most of the patients had colorectal cancer, but a cohort of 9 patients with dMMR tumors that were not colorectal was included. In the full cohort, mismatch-repair status predicted clinical benefit of pembrolizumab, and patients with dMMR noncolorectal cancer had responses similar to those of patients with dMMR colorectal cancer.

Patients with dMMR/MSI-H endometrial cancer (EC; n=103) or dMMR/MSI-H and/or polymerase epsilon (POLE)-mutant non-endometrial solid cancers (n=106) who had experienced disease progression for recurrent or advanced disease with no satisfactory alternative treatment options were evaluated in the multicenter, open-label GARNET trial, a phase 1 dose escalation and cohort expansion study of dostarlimab-gxly (Jemperli) (CDER, 2021). Laboratory-developed tests using immunohistochemistry (IHC), polymerase chain reaction (PCR), or next generation sequencing (NGS) were used to prospectively determine patient variant status, and dMMR status was retrospectively confirmed with the marketed companion diagnostic test, the Ventana MMR RxDx Panel, a qualitative IHC test. Accelerated drug approval was based on an overall response rate of 41.6% (95% CI, 34.9%, 48.6%) for the full cohort, the primary efficacy outcome, as assessed at data cutoff with a median follow-up duration of 13.5 months. The median duration of response was 34.7 months, with 95.4% of patients achieving a duration of response ≥ 6 months. The confirmed overall response rate was 44.7% (95% CI, 34.9% to 54.8%) and 38.7% (29.4% to 48.6%) for EC and non-EC cohorts, respectively. One patient with breast cancer was enrolled in the study and achieved a complete response and ongoing duration of response of 16.8 months. Continued drug approval is subject to the results of confirmatory trials.

In a phase 2 trial of pembrolizumab in 233 previously treated patients with MSI-H solid tumors, the overall response rate was 34.3% (95% CI, 28.3% to 40.8%). Median PFS was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). A phase 1 dose escalation study of dostarlimab-gxly reported an overall response rate of 41.6% with a median duration of response of 34.7 months for a combined cohort of 209 patients with endometrial cancer and non-endometrial cancer solid cancers; however, enrollment of patients with breast cancer was limited to 1 individual.

Ki-67 Testing

The Ki-67 IHC MIB-1 pharmDx (Dako Omnis) test is an FDA-approved companion diagnostic for abemaciclib (Verzenio).

Efficacy of abemaciclib was evaluated in the multicenter, randomized, open-label monarchE (NCT03155997) trial reported by Johnston and coworkers (Johnston, 2020). Adult men and women with HR-positive, HER2-negative, node-positive, early breast cancer with clinical and pathological features consistent with a high risk of recurrence were enrolled and randomized to receive either 2 years of abemaciclib plus physician's choice of standard endocrine therapy (n=2808) or endocrine therapy alone (n=2829). The primary efficacy outcome was invasive disease-free survival (IDFS). At the preplanned interim efficacy analysis, abemaciclib plus endocrine therapy demonstrated superior IDFS compared to endocrine therapy alone (HR, 0.75; 95% CI, 0.60 to 0.93; p=.01), with 2-year IDFS rates of 92.2% versus 88.75 respectively. Ki-67 index ≥ 20% was reported for 1262 (44.9%) and 1233 (43.6%) patients treated with abemaciclib plus endocrine therapy and endocrine therapy alone, respectively. In a secondary pre-planned efficacy analysis of patients with high risk of recurrence and retrospectively confirmed Ki-67 score ≥ 20% (n=2003), the study also demonstrated a statistically significant improvement in the primary efficacy outcome of IDFS (HR 0.626; 95% CI, 0.488-0.803; p=.0042). For patients receiving abemaciclib plus tamoxifen or an aromatase inhibitor, IDFS at 36 months was 86.1% (95% CI, 82.8% to 88.8%) compared to 79.0% at 36 months (95% CI, 75.3% to 82.3%) in patients receiving only tamoxifen or an aromatase inhibitor. At the time of IDFS, overall survival data was immature and not reported.

Efficacy of abemaciclib in the ITT population at median follow-up 19 months showed continued benefit in IDFS (HR = 0.71, 95% CI 0.58-0.87; nominal p<.001) with an absolute improvement of 3.0% in the 2-year IDFS rates (abemaciclib + ET: 92.3% versus ET alone: 89.3%), and benefit in DRFS (HR = 0.69, 95% CI 0.55 to 0.86; nominal p<.001) with absolute difference of 3.0% at 2 years (abemaciclib + ET: 93.8% versus ET alone: 90.8%) (Harbeck, 2021). At 27 months, the benefit of abemaciclib held (IDFS HR = 0.70, 95% CI 0.59 to 0.82; nominal p<.0001 and DRFS HR = 0.69, 95% CI 0.57 to 0.83; nominal p<.0001). When assessing Ki-67-high and -low populations, abemaciclib + ET showed an IDFS benefit regardless of the Ki-67 index and for all follow-up time periods assessed. The 3-year IDFS rates in the control arm suggested that patients with Ki-67-high tumors had a higher risk of developing an IDFS event than those with Ki-67-low tumors (79.0% versus 87.2%, respectively), thus indicating the prognostic value of Ki-67. While Ki-67 was prognostic, the abemaciclib benefit was observed regardless of Ki-67 status. The data for IDFS among patients with 1-3 positive ALNs, tumor size <5cm, grade < 3, and high Ki-67 index (over 20%) remained immature.

Among patients with HR-positive, HER2-negative, node-positive, early breast cancer with clinical and pathological features consistent with a high risk of recurrence (n=5637), abemaciclib plus endocrine therapy demonstrated superior invasive disease-free survival compared to endocrine therapy alone (HR=0.75; p=.01). For the cohort of patients with Ki-67 score ≥ 20% (n=2003 [35.5%]), secondary analysis of invasive disease-free survival was also superior for the group receiving abemaciclib (HR=0.626; p=.0042). However, additional analyses showed the abemaciclib benefit was observed regardless of Ki-67 status. Further study is necessary to confirm whether an improved overall survival benefit is observed among patients with Ki-67 positive status.

Tumor Mutational Burden

FoundationOne is an FDA approved companion diagnostic test to measure TMB in patients with solid tumors being considered for pembrolizumab treatment.

Ott et al reported an exploratory analysis of the association between TMB and response to pembrolizumab. All patients in the study were PD-L1 positive (Ott, 2019).

Marabelle et al reported the association of high TMB to response to pembrolizumab in patients with solid tumors enrolled in a prespecified exploratory analysis of the KEYNOTE-158 study (Marabelle, 2020). High TMB was defined as >10 mutations per megabase according to the FoundationOne CDx panel. The proportion of patients with an objective response in the tTMB-high group was 29%. At a median follow-up of approximately 3 years, the median duration of response was not reached in the tTMB-high group and was 33·1 months in the non-tTMB-high group. Notably, TMB-high status was associated with improved response irrespective of PD-L1. Median PFS and overall survival did not differ between the high and non-high TMB groups. Objective responses were observed in 24 (35%; 95% CI, 24–48) of 68 participants who had both tTMB-high status and PD-L1-positive tumours (ie, PD-L1 combined positive score of ≥1) and in 6 (21%; 8–40) of 29 participants who had tTMB-high status and PD-L1-negative tumors. The interpretation of these results is limited by the lack of enrollment of patients with breast cancer.

Alva et al reported results from the Targeted Agent and Profiling Utilization Registry (TAPUR), a phase II pragmatic basket trial evaluating the efficacy of FDA-approved targeted therapies in patients with advanced tumors that harbor a genomic variant known to be a drug target or to predict treatment response (Alva, 2021). In a cohort of 28 patients with metastatic breast cancer and TMB-H status treated with pembrolizumab, ten patients achieved disease control, defined as objective response or stable disease of at least 16 weeks duration, yielding a disease control rate of 37% (95% CI, 21% to 50%), a median PFS of 10.6 weeks (95% CI, 7.7 to 21.1 weeks), and a median overall survival of 30.6 weeks (95% CI, 18.3 to 103.3 weeks). The authors noted that TMB does not appear to be related to PFS or overall survival, but that the study was not powered to detect such an association. Additionally, TMB-H status was defined as ≥ 9 mut/Mb at the time of enrollment.

In a prespecified subgroup analysis of a nonrandomized trial of pembrolizumab in patients with various solid tumors, objective responses were observed in 24 (35%; 95% CI 24–48) of 68 participants who had both tTMB-high status and PD-L1-positive tumors and in 6 (21%; 8–40) of 29 participants who had tTMB-high status and PD-L1-negative tumors. In exploratory analyses, retrospective observational studies have reported an association between higher TMB and longer PFS and overall survival in patients receiving immunotherapy. These results need to be confirmed in additional, well-designed prospective studies.

Circulating Tumor DNA Testing

FoundationOne Liquid is FDA approved as a companion diagnostic test for alpelisib (Piqray) for measuring 11 variants in the PIK3CA gene.

Woodhouse reported the clinical validity of FoundationOne liquid for detection of PIK3CA alterations through retrospective testing of plasma samples of patients enrolled in the SOLAR-1 trial (Woodhouse, 2020).

All available plasma samples from patients collected at baseline prior to randomization into the SOLAR-1 clinical trial were tested with FoundationOne Liquid CDx, with results compared to tissue genotyping performing using the SOLAR-1 CTA. The positive predictive agreement and negative predictive agreement between FoundationOne Liquid CDx and the tissue-based CTA assay were 71.7% (95% CI 65.4%, 77.5%) and 100% (97.2%, 100%), respectively.

In the SOLAR-1 trial (discussed above in the section on PIK3CA testing), the clinical efficacy of alpelisib in combination with fulvestrant for the FoundationOne Liquid CDx-positive population was demonstrated with an estimated 54% risk reduction in disease progression or death in the alpelisib plus fulvestrant arm compared to the placebo plus fulvestrant arm (HR = 0.46, 95% CI, 0.30, 0.70) (Andre, 2019).

Clinical validity of the FoundationOne Liquid CDx test was demonstrated through retrospective testing of plasma samples of patients enrolled in the SOLAR-1 trial. The positive predictive agreement and negative predictive agreement between FoundationOne Liquid CDx and the tissue-based assay were 71.7% (95% CI 65.4%, 77.5%) and 100% (97.2%, 100%), respectively. Among the circulating tumor DNA-positive population, there was an estimated 54% risk reduction in disease progression or death in the alpelisib plus fulvestrant arm compared to the placebo plus fulvestrant arm (HR = 0.46, 95% CI, 0.30, 0.70).

Circulating Tumor Cell Testing

Two RCTs have evaluated the clinical utility of using CTC to guide treatment decisions in patients with metastatic breast cancer.

Smerage et al reported on the results of an RCT of patients with metastatic breast cancer and persistently increased CTC levels to test whether changing chemotherapy after 1 cycle of first-line therapy could improve overall survival (Smerage, 2014). Level of CTCs were enumerated using the CellSearch system. Five or more CTCs per 7.5 mL WB was considered an increased level, and it served as the cut point for separation of favorable versus unfavorable prognosis. Patients who did not have increased CTC levels at baseline remained on initial therapy until progression (arm A), patients with initially increased CTC levels that decreased after 21 days of therapy remained on initial therapy (arm B), and patients with persistently increased CTC levels after 21 days of therapy were randomized to continue initial therapy (arm C1) or change to an alternative chemotherapy (arm C2). There were 595 eligible and evaluable patients, 276 (46%) of whom did not have increased CTC levels (arm A). Of patients with initially increased CTC levels, 31 (10%) were not retested, 165 were assigned to arm B, and 123 were randomized to arms C1 or C2. There was no difference in median overall survival between arms C1 (10.7 months) and C2 12.5 months; p=0.98). CTC levels were strongly prognostic, with a median overall survival for arms A, B, and C (C1 and C2 combined) of 35 months, 23 months, and 13 months, respectively (p<.001). While the trial showed the prognostic significance of CTCs in patients with metastatic breast cancer, changing to an alternative chemotherapeutic regimen did not improve outcomes in patients whose CTCs were not reduced after 1 cycle of first-line chemotherapy.

More recently, Bidard et al reported on a noninferiority trial comparing CTC-driven vs clinician driven first-line therapy choice in patients with metastatic breast cancer (Bidard, 2021). Median PFS was 15.5 months (95% CI, 12.7-17.3) in the CTC arm and 13.9 months (95% CI, 12.2-16.3) in the standard arm. The primary end point was met, with a hazard ratio of 0.94 (90% CI, 0.81-1.09).

Systematic reviews and meta-analyses have described an association between CTCs and poor prognosis in metastatic breast cancer, but evidence that CTC-driven treatment improves health outcomes is lacking. One RCT found no improvement in overall survival or PFS with CTC-driven treatment (early switching to a different chemotherapy regimen) compared to continuing initial therapy. A second RCT found that CTC-driven first-line therapy was noninferior to clinician-driven therapy in previously untreated patients with metastatic breast cancer (hazard ratio for PFS 0.94; 95% CI 0.81 to 1.09).

Summary of Evidence

For individuals with metastatic or high-risk, early stage HER2-negative breast cancer being considered for systemic therapy (ie, poly(adenosine diphosphate–ribose) polymerase [PARP] inhibitors) who receive genetic testing for a BRCA1 or BRCA2 germline variant, the evidence includes randomized, placebo-controlled trials of olaparib and talazoparib. Relevant outcomes are overall survival, disease-specific survival, test validity, quality of life, and treatment-related morbidity. In individuals with a BRCA1/2 mutation and either HER2-negative metastatic breast cancer or other advanced breast cancer who were followed for 11-12 months, treatment with a PARP inhibitor drug resulted in a 40% to 46% lower risk of disease progression or death. In individuals with a BRCA1/2 mutation and early-stage breast cancer at high-risk for recurrence, treatment with olaparib resulted in a 9% improvement in 3-year invasive disease-free survival. Therefore, knowledge of BRCA variant status in individuals diagnosed with breast cancer may impact treatment decisions. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with hormone receptor-positive, HER2 negative advanced or metastatic breast cancer who receive PIK3CA gene testing to select targeted treatment, the evidence includes a randomized, placebo-controlled trial of alpelisib compared to placebo in men and postmenopausal women with advanced breast cancer who had previously received endocrine therapy. Relevant outcomes include overall survival, disease-specific survival, test validity, quality of life, and treatment-related morbidity. Among patients with PIK3CA-positive tumors who received targeted therapy, PFS was 11.0 months (95% CI, 7.5 to 14.5), compared to 5.7 months (95% CI, 3.7 to 7.4) in PIK3CA-positive patients who received standard care. In contrast, the hazard ratio for PFS in the cohort without PIK3CA-mutated cancer was not significantly different for the active vs placebo groups. The overall response rate was higher in patients with PIK3CA-positive tumors compared to the rate in the standard care group (26.6% [95% CI 20.1- 34.0] vs 12.8% [8.2-18.7%]). The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with locally advanced or metastatic breast cancer being considered for immunotherapy who receive NTRK gene fusion testing, the evidence includes integrated analyses of nonrandomized trials of larotrectinib and entrectinib in patients with NTRK-fusion positive solid tumors. Relevant outcomes are overall survival, disease-specific survival, test validity, quality of life, and treatment-related morbidity. In an analysis of 159 patients with NTRK-fusion positive solid tumors who received larotrectinib, including 5 patients with breast tumors, the overall response rate was 79% (95% CI 72 to 85). The median PFS was 28·3 months (95% CI 22.·1 to not estimable), and 67% of patients were progression-free at 12 months (95% CI 58–76). In an integrated analysis of 3 phase 1-2 trials in 54 patients with NTRK-positive solid tumors who received entrectinib, 6 of whom had breast cancer, the overall response rate was 57% (95% CI, 43.2–70.8). At data cutoff, 16 (30%) of 54 patients had died, and the estimated median overall survival was 21 months (95% CI, 14.9 to not estimable. Responses were observed regardless of tumor type or age of the patient. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with recurrent, metastatic, or unresectable hormone receptor-negative, HER2 negative (triple negative) breast cancer being considered for immunotherapy who receive PD-L1 testing, the evidence includes a RCT of atezolizumab and nonrandomized trials of pembrolizumab. Relevant outcomes include overall survival, disease-specific survival, test validity, quality of life, and treatment-related morbidity. In a placebo controlled trial of atezolizumab in combination with nab-paclitaxel for patients with PD-L1 positive TNBC, median PFS (HR 0.62; 95% CI, 0.49 to 0.78) and overall survival 0.62 (95% CI, 0.45–0.86) were longer among patients who received the targeted immunotherapy. However, these findings were not confirmed in a designated confirmatory trial and accelerated approval was withdrawn for atezolizumab. In 2 nonrandomized trials of pembrolizumab for patients with PD-L1 positive TNBC, the objective response rate was 21.4% (95% CI, 13.9 to 31.4) and 18.5% (95% CI, 6.3 to 38.1). In 1 randomized trial of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for patients with TNBC and PD-L1 combined positive score ≥10, the median PFS was 9.7 and 5.6 months, respectively (HR, 0.65; 95% CI, 0.49 to 0.86). The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with unresectable or metastatic breast cancer who are being considered for pembrolizumab therapy who receive MSI-H/dMMR testing, the evidence includes nonrandomized trials in patients with solid tumors. Relevant outcomes include overall survival, disease-specific survival, test validity, quality of life, and treatment-related morbidity. In a phase 2 trial of pembrolizumab in 233 previously treated patients with MSI-H solid tumors, the overall response rate was 34.3% (95% CI, 28.3% to 40.8%). Median PFS was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with recurrent or advanced breast cancer who are being considered for dostarlimab-gxly therapy who receive dMMR testing, the evidence includes nonrandomized trials in patients with solid tumors. Relevant outcomes include overall survival, disease-specific survival, test validity, quality of life, and treatment-related morbidity. A phase 1 dose escalation study of dostarlimab-gxly reported an overall response rate of 41.6% with a median duration of response of 34.7 months for a combined cohort of 209 patients with endometrial cancer and non-endometrial cancer solid cancers; however, enrollment of patients with breast cancer was limited to 1 individual. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with breast cancer who are being considered for abemaciclib therapy who receive Ki-67 testing, the evidence includes a randomized, controlled, open-label trial. Relevant outcomes include overall survival, disease-specific survival, test validity, quality of life, and treatment-related morbidity. Among patients with hormone receptor-positive, HER2-negative, node-positive, early breast cancer with clinical and pathological features consistent with a high risk of recurrence (n=5637), abemaciclib plus endocrine therapy demonstrated superior invasive disease-free survival compared to endocrine therapy alone (HR=0.75; p=.01). For the cohort of patients with Ki-67 score ≥ 20% (n=2003 [35.5%]), secondary analysis of invasive disease-free survival was also superior for the group receiving abemaciclib (HR=0.626; p=.0042). However, additional analyses showed the abemaciclib benefit was observed regardless of Ki-67 status. Further study is necessary to confirm whether an improved overall survival benefit is observed among patients with Ki-67 'high' versus 'low' status. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with unresectable or metastatic breast cancer who are being considered for immunotherapy who receive tumor mutational burden (TMB) testing, the evidence includes prospective and retrospective subgroup analyses of nonrandomized trials. Relevant outcomes include overall survival, disease-specific survival, test validity, quality of life, and treatment-related morbidity. In a prespecified subgroup analysis of a nonrandomized trial of pembrolizumab in patients with various solid tumors, objective responses were observed in 24 (35%; 95% CI, 24–48) of 68 participants who had both tTMB-high status and PD-L1-positive tumors and in 6 (21%; 8–40) of 29 participants who had tTMB-high status and PD-L1-negative tumors. In exploratory analyses, retrospective observational studies have reported an association between higher TMB and longer PFS and overall survival in patients receiving immunotherapy. These results need to be confirmed in additional, well-designed prospective studies enrolling patients with breast cancer. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with hormone receptor-positive, HER2 negative advanced or metastatic breast cancer who receive circulating tumor DNA testing to select targeted treatment, the evidence includes a randomized, placebo-controlled trial of alpelisib compared to placebo in men and postmenopausal women with advanced breast cancer who had previously received endocrine therapy. Relevant outcomes include overall survival, disease-specific survival, test validity, quality of life, and treatment-related morbidity. Clinical validity of the FoundationOne Liquid CDx test was demonstrated through retrospective testing of plasma samples of patients enrolled in the SOLAR-1 trial. The positive predictive agreement and negative predictive agreement between FoundationOne Liquid CDx and the tissue-based assay were 71.7% (95% CI, 65.4%, 77.5%) and 100% (97.2%, 100%), respectively. Among the circulating tumor DNA-positive population, there was an estimated 54% risk reduction in disease progression or death in the alpelisib plus fulvestrant arm compared to the placebo plus fulvestrant arm (HR = 0.46, 95% CI, 0.30, 0.70). The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with metastatic breast cancer who receive CTC testing to guide treatment decisions, the evidence includes RCTs, observational studies, and systematic reviews. Relevant outcomes include overall survival, disease-specific survival, test validity, quality of life, and treatment-related morbidity. Systematic reviews and meta-analyses have described an association between CTCs and poor prognosis in metastatic breast cancer, but evidence that CTC-driven treatment improves health outcomes is lacking. One RCT found no improvement in overall survival or PFS with CTC-driven treatment (early switching to a different chemotherapy regimen) compared to continuing initial therapy. A second RCT found that CTC-driven first-line therapy was noninferior to clinician-driven therapy in previously untreated patients with metastatic breast cancer (hazard ratio for PFS 0.94; 95% CI 0.81 to 1.09). The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

National Comprehensive Cancer Network guidelines (v.1.2022) on biomarker testing for targeted treatment of breast cancer is summarized below. The guidelines state that the use of circulating tumor cells or circulating tumor DNA in metastatic breast cancer is not yet included in algorithms for disease assessment and monitoring. For patients being considered for treatment with alpelisib, testing for PIK3CA with either tissue or liquid biopsy is recommended (category of evidence 2A).

National Comprehensive Cancer Network Guidelines on Biomarker Testing for Targeted Treatment of Breast Cancer (NCCN, 2022)

BRCA1/2 mutations

Breast Cancer Subtype: any
FDA approved agents: Olaparib and Talazoparib
Testing recommendation: Patients with recurrent or metastatic breast cancer should be assessed for BRCA1/2 mutations with germline sequencing to identify candidates for PARP inhibitor therapy. While olaparib and talazoparib are FDA-indicated in HER2-negative disease, NCCN supports use in any breast cancer subtype associated with a germline BRCA1 or BRCA2 mutation.
Targeted Therapy Category of Evidence: 1
Targeted Therapy Category of Preference: Preferred

PIK3CA

Breast Cancer Subtype: HR-positive/HER2-negative
FDA approved agents: Alpelisib + fulvestrant
Testing recommendation: For HR-positive/HER2-negative breast cancer, assess for PIK3CA mutations with tumor or liquid biopsy to identify candidates for alpelisib plus fulvestrant. PIK3CA mutation testing can be done on tumor tissue or ctDNA in peripheral blood (liquid biopsy). If liquid biopsy is negative, tumor tissue testing is recommended
Targeted Therapy Category of Evidence: 1
Targeted Therapy Category of Preference: Preferred second or subsequent line therapy

PD-L1 expression (combined positive score > 10)

Breast Cancer Subtype: Triple negative
FDA approved agents: Pembrolizumab + chemotherapy (albumin-bound paclitaxel, or gemcitabine and carboplatin)
Testing recommendation: For triple-negative breast cancer, assess PD-L1 expression using 22C3 antibody via immunohistochemistry. While available data are in the first-line setting, this regimen can be used for second and subsequent lines of therapy if PD-1/PD-L1 inhibitor therapy has not been previously used.
Targeted Therapy Category of Evidence: 1
Targeted Therapy Category of Preference: Preferred first line therapy

NTRK fusion

Breast Cancer Subtype: Any
FDA approved agents: Larotrectinib and Entrectinib
Testing recommendation: No specific testing recommendation. If a patient with recurrent/stage IV breast cancer presents with a tumor with an NTRK fusion, treatment with an NTRK inhibitor is an option if no satisfactory alternative treatments exist or that have progressed following treatment, treatment with an NTRK inhibitor is an option.
Targeted Therapy Category of Evidence: 2A
Targeted Therapy Category of Preference: Useful in certain circumstances

MSI-H/dMMR

Breast Cancer Subtype: Any
FDA approved agents: Pembrolizumab and Dostarlimab-gxly
Testing recommendation: Biomarker detection via immunohistochemistry or PCR tissue block is recommended. If a patient with unresectable or metastatic MSI-H/dMMR breast cancer has progressed on or following prior treatment with no satisfactory alternative treatment options, pembrolizumab or dostarlimab-gxly are indicated.
Targeted Therapy Category of Evidence: 2A
Targeted Therapy Category of Preference: Useful in certain circumstances

TMB-H (≥10 mut/mb)

Breast Cancer Subtype: Any
FDA approved agents: Pembrolizumab
Testing recommendation: Biomarker detection via NGS is indicated in patients with unresectable or metastatic TMB-H tumors that have progressed following prior treatment and who have no satisfactory treatment options.
Targeted Therapy Category of Evidence: 2A
Targeted Therapy Category of Preference: Useful in certain circumstances

In January 2020, the Centers for Medicare and Medicaid Services (CMS) determined that next-generation sequencing (NGS) is covered for patients with breast or ovarian cancer when the diagnostic test is performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory AND the test has approval or clearance by the U.S. Food and Drug Administration (CAG-00450R) (CMS, 2020).

CMS states that local Medicare carriers may determine coverage of NGS for management of the patient for any cancer diagnosis with a clinical indication and risk factor for germline testing of hereditary cancers when performed in a CLIA-certified laboratory.

Ongoing and Unpublished Clinical Trials:

NCT04098640 Molecular Profiling Using FoundationOne CDx in Young (<50 Years of Age) Patients With Metastatic Breast Cancer (ML41263) has a planned enrollment of 200 and anticipated completion date of July 2021
NCT03197935a A Phase III Randomized Study to Investigate the Efficacy and Safety of Atezolizumab (Anti-PD-L1 Antibody) in Combination With Neoadjuvant Anthracycline/Nab-Paclitaxel-Based Chemotherapy Compared With Placebo and Chemotherapy in Patients With Primary Invasive Triple-Negative Breast Cancer (IMpassion031) has a planned enrollment of 333 and anticipated completion date of October 2022
NCT03145961a c-TRAK TN: A Randomised Trial Utilising ctDNA Mutation Tracking to Detect Minimal Residual Disease and Trigger Intervention in Patients With Moderate and High Risk Early Stage Triple Negative Breast Cancer has a planned enrollment of 208 and anticipated completion date of December 2022
NCT03213041a I-CURE-1: A Phase II, Single Arm Study of Pembroluzimab Combined With Carboplatin in Patients With Circulating Tumor Cells (CTCs) Positive HER-2 Negative Metastatic Breast Cancer (MBC) has a planned enrollment of 100 and anticipated completion date of July 2023 (recruiting)
NCT02965755a Individualized Molecular Analyses Guide Efforts in Breast Cancer - Personalized Molecular Profiling in Cancer Treatment at Johns Hopkins (IMAGE-II) has a planned enrollment of 200 and anticipated completion date of July 2023 (recruiting)
NCT02819518a A Randomized, Double-Blind, Phase III Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs Placebo Plus Chemotherapy for Previously Untreated Locally Recurrent Inoperable or Metastatic Triple Negative Breast Cancer (KEYNOTE-355) has a planned enrollment of 882 and anticipated completion date of November 2023
NCT02889978a The Circulating Cell-free Genome Atlas Study (CCGA) has a planned enrollment of 15,000 and an anticipated completion date of March 2024
NCT02568267a An Open-Label, Multicenter, Global Phase 2 Basket Study of Entrectinib for the Treatment of Patients With Locally Advanced or Metastatic Solid Tumors That Harbor NTRK1/2/3, ROS1, or ALK Gene Rearrangements (STARTRK-2) has a planned enrollment of 700 and an anticipated completion date of December 2024 (recruiting)
NCT04591431 The Rome Trial - From Histology to Target: the Road to Personalize Target Therapy and Immunotherapy has a planned enrollment of 384 and an anticipated completion date of August 2024 (recruiting)
NCT02693535a Targeted Agent and Profiling Utilization Registry (TAPUR) Study has a planned enrollment of 3,581 and an anticipated completion date of December 2024 (recruiting)
NCT04720729 Chemotherapy Monitoring by Circulating Tumor DNA (ctDNA) in HER2 (Human Epidermal Growth Factor Receptor-2)- Metastatic Breast Cancer (MONDRIAN): a Phase 2 Study has a planned enrollment of 214 and an anticipated completion date of June 2025 (recruiting)
NCT04526587 The Roswell Park Ciclib Study: A Prospective Study of Biomarkers and Clinical Features of Advanced/Metastatic Breast Cancer Treated With CDK4/6 Inhibitors has a planned enrollment of 300 and an anticipated completion date of July 2025 (recruiting)
NCT04895358a A Randomized, Double-blind, Placebo-controlled, Phase 3 Study of Pembrolizumab Plus Chemotherapy Versus Placebo Plus Chemotherapy for the Treatment of Chemotherapy-Candidate Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative (HR+/HER2-) Locally Recurrent Inoperable or Metastatic Breast Cancer (KEYNOTE-B49) has a planned enrollment of 800 and an anticipated completion date of October 2027 (recruiting)
NCT02306096 SCAN-B: The Sweden Cancerome Analysis Network - Breast Initiative has a planned enrollment of 20,000 and an anticipated completion date of August 2031 (recruiting)

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through October 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

The efficacy of pembrolizumab plus chemotherapy compared to placebo plus chemotherapy for previously untreated, locally recurrent inoperable or metastatic triple-negative breast cancer (N=847) was evaluated in the KEYNOTE-355 study.Dual primary efficacy endpoints were PFS and overall survival in patients with PD-L1 combined positive score ≥1. Interim study results were published in 2020, and final results were published in 2022 (Cortes, 2020; Cortes 2022). This study formed the basis of pembrolizumab accelerated approval in patients with unresectable or metastatic triple-negative breast cancer and PD-L1 CPS ≥10.

The efficacy of selpercatinib in patients with tumor-agnostic RET fusion-positive advanced solid tumors was evaluated in a subset of the phase 1/2 LIBRETTO-001 basket trial (NCT03157128) reported by Subbiah et al (Subbiah, 2022). LIBRETTO-001 included adult patients with solid tumors with a life expectancy of at least 3 months and with disease progression on or after previous systemic therapies or who had no satisfactory therapeutic options. RET alteration status was determined by local molecular testing performed in a certified laboratory with the use of next-generation sequencing, fluorescence in situ hybridization (FISH), or polymerase-chain-reaction (PCR) assay (Drilon, 2020). Of the 45 patients included in the trial, 4% (2/45) had primary breast cancer; 4 patients were excluded from efficacy analyses though none of these were breast cancer patients. The primary outcome was overall response rate (complete or partial response) assessed according to independent review using Response Evaluation Criteria in Solid Tumours (RECIST) criteria, version 1.1. In the total population, overall response was 43.9% (95% CI 28.5 to 60.3) and the median duration of response was 24.5 months. In the 2 breast cancer patients, the response rate was 100% (95% CI 15.8 to 100) and the median duration of response was 17.3 months. Harms of treatment were reported for the total cohort; 3 patients had serious, treatment-related adverse events, and elevated liver enzymes (AST and ALT) were the most common grade 3 or higher adverse events. LIBRETTO-001 is ongoing, and continued selpercatinib approval in this population is subject to the results of confirmatory trials.

Salama et al reported on the NCI MATCH Subprotocol H (NCT02465060) in the USA (Salama, 2020). The sites are unclear for Subprotocol H. This study was an open-label, single-arm, basket trial that took place between August 2015 to February 2018. There were 35 participants (none with breast cancer). Participants had BRAF V600E mutated solid tumors, lymphoma, or multiple myeloma with disease progression on at least 1 standard therapy and measurable disease according to standard practice for the tumor type. The median age was 59 years. 62% female. Participants consisted of 93% white, 1% Black, 1% mixed race, and 1% not reported. Intervention consisted of Dabrafenib 150 mg 2x/day and trametinib 2 mg/day. Overall response N=29 38% (23 to 55; all partial response, no patients had complete response). Duration of response N=29 Median 25.1 months (12.8 to NA). PFS N=29 Median 11.4 months (7.2 to 16.3). Overall survival N=29 Median 28.6 months (not reported). Treatment related adverse events N=35 Grade 4 adverse event: 3% (1/35) Grade 3 adverse event: 63% (22/35).

Subbiah et al reported on the BRF117019 (NCT02034110) study (Subbiah, 2020). It took place at 19 sites in 9 countries (USA and Europe). The study took place between March 2014-July 2018. It was an open-label, single-arm, phase 2 basket trial with 43 (none with breast cancer) participants. Participants had BRAF V600E mutated biliary tract cancer that was unresectable, metastatic, locally advanced, or recurrent with no other standard treatment options available. The mean age was 57 years. 56% of participants were female. 93% were white, and 7% were Asian. Intervention consisted of abrafenib 150 mg 2x/day and trametinib 2 mg/day. Overall response N=43 47% (31 to 62; all partial response, no patients had complete response). Duration of response N=22 Median 9 months (6 to 14). PFS N=43 Median 9 months (5 to 10). Overall survival N=43 Median 14 months (10 to 33). Treatment related adverse events Serious treatment-related adverse event: 21% (9/43).

Wen et al reported on the BRF117019 (NCT02034110) study which took place at 27 sites in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, USA) (Wen, 2022). It took place between April 2014-July 2018. It is an open-label, single-arm, phase 2 basket trial with 58 participants (none with breast cancer; 45 high-grade glioma, 13 low-grade glioma). Participants were diagnosed with BRAF V600E mutated high- or low-grade glioma. For high-grade glioma, the mean age was 42 years. 49% were female. 76% were white, 13% were Asian, 4% were Black, 2% were American Indian or Alaska Native, and 4% were not reported. For low-grade glioma, the mean age was 33 years and 69% were female. 77% were white and 33% were Asian. Intervention consisted of Dabrafenib 150 mg 2x/day and trametinib 2 mg/day. Overall response N=45 high-grade glioma cohort N=13 low-grade glioma cohort High-grade cohort: 31% (18 to 47; 7% had complete response) Low-grade cohort: 69% (39 to 91; 8% had complete response). Duration of response N=45 high-grade glioma cohort N=13 low-grade glioma cohort High-grade cohort: median 13.6 months (4.6 to 43.4) Low-grade cohort: median 27.5 months (3.8 to 39.5). PFS N=45 high-grade glioma cohort

N=13 low-grade glioma cohort High-grade cohort: median 4.5 months (1.8 to 7.4) Low-grade cohort: median 14.0 months (4.7 to 46.9). Overall survival N= N=45 high-grade glioma cohort N=13 low-grade glioma cohort High-grade cohort: median 17.6 months (9.5 to 45.2) Low-grade cohort: median not reported. Treatment-related adverse event: N=58 Serious treatment-related adverse events: 12% (7/45).

Systematic reviews and meta-analyses have described an association between CTCs and poor prognosis in metastatic breast cancer (Bidard, 2014; Lu, 2016).

In 2022, the American Society of Clinical Oncology published an updated guideline on biomarker testing to guide systemic therapy in patients with metastatic breast cancer (Henry, 2022). The guideline recommended the following biomarker tests:

PIK3CA (Type of recommendation: evidence-based; Evidence quality: high; Strength of recommendation: strong)
Germline BRCA1 and BRCA2 (Type of recommendation: evidence-based; Evidence quality: high; Strength of recommendation: strong)
PD-L1 (Type of recommendation: evidence-based; Evidence quality: intermediate; Strength of recommendation: strong)
MSI-H/dMMR (Type of recommendation: informal consensus-based; Evidence quality: low; Strength of recommendation: moderate)
TMB (Type of recommendation: informal consensus-based; Evidence quality: low; Strength of recommendation: moderate)
NTRK fusions (Type of recommendation: informal consensus-based; Evidence quality: low; Strength of recommendation: moderate)

The following biomarker tests were not recommended by ASCO: ERI1, PALB2, TROP2 expression, circulating tumor DNA, circulating tumor cell.

Detailed recommendations are as follows:

Patients with locally recurrent unresectable or metastatic hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer who are candidates for a treatment regimen that includes a phosphatidylinositol 3-kinase inhibitor and a hormonal therapy should undergo testing for PIK3CA mutations using next-generation sequencing of tumor tissue or circulating tumor DNA (ctDNA) in plasma to determine their eligibility for treatment with the phosphatidylinositol 3-kinase inhibitor alpelisib plus fulvestrant. If no mutation is found in ctDNA, testing in tumor tissue, if available, should be used as this will detect a small number of additional patients with PIK3CA mutations (Type of recommendation: evidence-based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong).
There are insufficient data at present to recommend routine testing for ESR1 mutations to guide therapy in hormone receptor–positive, HER2-negative MBC. Existing data suggest reduced efficacy of aromatase inhibitors (AIs) compared with the selective estrogen receptor degrader fulvestrant in patients who have tumor or ctDNA with ESR1 mutations (Type of recommendation: informal consensus; Evidence quality: insufficient; Strength of recommendation: moderate).
Patients with metastatic HER2-negative breast cancer who are candidates for treatment with a poly (ADP-ribose) polymerase (PARP) inhibitor should undergo testing for germline BRCA1 and BRCA2 pathogenic or likely pathogenic mutations to determine their eligibility for treatment with the PARP inhibitors olaparib or talazoparib (Type of recommendation: evidence-based, benefits outweigh harms; Evidence quality: high; Strength of recommendation: strong).
There is insufficient evidence to support a recommendation either for or against testing for a germline PALB2 pathogenic variant for the purpose of determining eligibility for treatment with PARP inhibitor therapy in the metastatic setting. This recommendation is independent of the indication for testing to assess cancer risk (Type: informal consensus; Evidence quality: low; Strength of recommendation: moderate).

Small single-arm studies show that oral PARP inhibitor therapy demonstrates high response rates in MBC encoding DNA repair defects, such as germline PALB2 pathogenic variants and somatic BRCA1/2 mutations. It should also be noted that the randomized PARP inhibitor trials made no direct comparison with taxanes, anthracyclines, or platinums; comparative efficacy against these compounds is unknown. There are insufficient data at present to recommend routine testing of tumors for homologous recombination deficiency to guide therapy for MBC (Type: informal consensus; Evidence quality: low; Strength of recommendation: moderate).

Patients with locally recurrent unresectable or metastatic hormone receptor-negative and HER2-negative breast cancer who are candidates for a treatment regimen that includes an immune checkpoint inhibitor (ICI) should undergo testing for expression of programmed cell death ligand-1 in the tumor and immune cells with a US Food and Drug Administration–approved test to determine eligibility for treatment with the ICI pembrolizumab plus chemotherapy (Type of recommendation: evidence based, benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: strong).
Patients with metastatic cancer who are candidates for a treatment regimen that includes an ICI should undergo testing for deficient mismatch repair/microsatellite instability-high to determine eligibility for dostarlimab-gxly or pembrolizumab (Type of recommendation: informal consensus; Evidence quality: low; Strength of recommendation: moderate).
Patients with metastatic cancer who are candidates for treatment with an ICI should undergo testing for tumor mutational burden to determine eligibility for pembrolizumab monotherapy (Type of recommendation: informal consensus; Evidence quality: low; Strength of recommendation: moderate).
Clinicians may test for NTRK fusions in patients with metastatic cancer who are candidates for a treatment regimen that includes a TRK inhibitor to determine eligibility for larotrectinib or entrectinib (Type of recommendation: informal consensus; Evidence quality: low; Strength of recommendation: moderate).
There are insufficient data to recommend routine testing of tumors for TROP2 expression to guide therapy with an anti-TROP2 antibody-drug conjugate for hormone receptor-negative, HER2-negative MBC (Type of recommendation: informal consensus; Evidence quality: low; Strength of recommendation: moderate).
There are insufficient data to recommend routine use of ctDNA to monitor response to therapy among patients with MBC (Type of recommendation: informal consensus; Evidence quality: low; Strength of recommendation: moderate).
There are insufficient data to recommend routine use of circulating tumor cells to monitor response to therapy among patients with MBC (Type of recommendation: informal consensus; Evidence quality: low; Strength of recommendation: moderate).

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

An interim analysis of overall survival, a secondary outcome in monarchE, was published in a letter to the editor by Harbeck et al in February 2022 (Harbeck, 2022). At 27 months, overall survival in the ITT population was 3.4% (96/2808) with abemaciclib + ET versus 3.2% (90/2829) in the ET alone (HR, 1.09, 95% CI 0.82 to 1.46). When limited to the abemaciclib FDA-indicated population (HR+, HER2-negative, node-positive, early breast cancer at high risk of recurrence, Ki-67 score of ≥20%) overall survival was 4.1% (42/1017) in the abemaciclib + ET and 5.4% (53/986) in the ET alone groups (HR, 0.77, 95% CI 0.51 to 1.15). An updated interim analysis of monarchE was published in 2023 (Johnston, 2023). With median follow-up of 42 months, median IDFS had not been reached in either group, and previously-identified IDFS (HR=0.664; 95% CI, 0.578 to 0.762) and DRFS benefits (HR=0.659; 95% CI, 0.567 to 0.767) appeared to be sustained. Subgroup analysis indicated similar IDFS and DRFS benefit with the addition of abemaciclib regardless of Ki-67 status. Overall survival data remained immature and did not indicate a difference between groups. The monarchE trial is ongoing with an estimated study completion date of June 2029...

CPT/HCPCS:

0037U	Targeted genomic sequence analysis, solid organ neoplasm, DNA analysis of 324 genes, interrogation for sequence variants, gene copy number amplifications, gene rearrangements, microsatellite instability and tumor mutational burden
0048U	Oncology (solid organ neoplasia), DNA, targeted sequencing of protein coding exons of 468 cancer associated genes, including interrogation for somatic mutations and microsatellite instability, matched with normal specimens, utilizing formalin fixed paraffin embedded tumor tissue, report of clinically significant mutation(s)
0155U	Oncology (breast cancer), DNA, PIK3CA (phosphatidylinositol 4,5 bisphosphate 3 kinase, catalytic subunit alpha) (eg, breast cancer) gene analysis (ie, p.C420R, p.E542K, p.E545A, p.E545D [g.1635G>T only], p.E545G, p.E545K, p.Q546E, p.Q546R, p.H1047L, p.H1047R, p.H1047Y), utilizing formalin fixed paraffin embedded breast tumor tissue, reported as PIK3CA gene mutation status
0177U	Oncology (breast cancer), DNA, PIK3CA (phosphatidylinositol 4,5 bisphosphate 3 kinase catalytic subunit alpha) gene analysis of 11 gene variants utilizing plasma, reported as PIK3CA gene mutation status
0211U	Oncology (pan-tumor), DNA and RNA by next-generation sequencing, utilizing formalin-fixed paraffin-embedded tissue, interpretative report for single nucleotide variants, copy number alterations, tumor mutational burden, and microsatellite instability, with therapy association
0239U	Targeted genomic sequence analysis panel, solid organ neoplasm, cell free DNA, analysis of 311 or more genes, interrogation for sequence variants, including substitutions, insertions, deletions, select rearrangements, and copy number variations
0242U	Targeted genomic sequence analysis panel, solid organ neoplasm, cell-free circulating DNA analysis of 55-74 genes, interrogation for sequence variants, gene copy number amplifications, and gene rearrangements
0409U	Oncology (solid tumor), DNA (80 genes) and RNA (36 genes), by next-generation sequencing from plasma, including single nucleotide variants, insertions/deletions, copy number alterations, microsatellite instability, and fusions, report showing identified mutations with clinical actionability
81191	NTRK1 (neurotrophic receptor tyrosine kinase 1) (eg, solid tumors) translocation analysis
81192	NTRK2 (neurotrophic receptor tyrosine kinase 2) (eg, solid tumors) translocation analysis
81193	NTRK3 (neurotrophic receptor tyrosine kinase 3) (eg, solid tumors) translocation analysis
81194	NTRK (neurotrophic tropomyosin receptor tyrosine kinase 1, 2, and 3) (eg, solid tumors) translocation analysis
81301	Microsatellite instability analysis (eg, hereditary non polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (eg, BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed
81309	PIK3CA (phosphatidylinositol 4, 5 biphosphate 3 kinase, catalytic subunit alpha) (eg, colorectal and breast cancer) gene analysis, targeted sequence analysis (eg, exons 7, 9, 20)
81445	Targeted genomic sequence analysis panel, solid organ neoplasm, DNA analysis, and RNA analysis when performed, 5 50 genes (eg, ALK, BRAF, CDKN2A, EGFR, ERBB2, KIT, KRAS, NRAS, MET, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed; DNA analysis or combined DNA and RNA analysis
81449	Targeted genomic sequence analysis panel, solid organ neoplasm, 5-50 genes RNA analysis
81455	Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm, DNA analysis, and RNA analysis when performed, 51 or greater genes (eg, ALK, BRAF, CDKN2A, CEBPA, DNMT3A, EGFR, ERBB2, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MLL, NPM1, NRAS, MET, NOTCH1, PDGFRA, PDGFRB, PGR, PIK3CA, PTEN, RET), interrogation for sequence variants and copy number variants or rearrangements, if performed; DNA analysis or combined DNA and RNA analysis
81456	Targeted genomic sequence analysis panel, solid organ or hematolymphoid neoplasm or disorder, 51 or greater genes RNA analysis
81479	Unlisted molecular pathology procedure

References:

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Albanell J, Elvin JA, Suh J, et al.(2016) BRAF Genetic Alterations in Breast Cancer. Ann Oncol. October 1 2016; 27(Supp 6): v170.

Alva AS, Mangat PK, Garrett-Mayer E, et al.(2021) Pembrolizumab in Patients With Metastatic Breast Cancer With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study. J Clin Oncol. Aug 01 2021; 39(22): 2443-2451. PMID 33844595

Andre F, Ciruelos E, Rubovszky G, et al.(2019) Alpelisib for PIK3CA -Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N Engl J Med. May 16 2019; 380(20): 1929-1940. PMID 31091374

Bidard FC, Jacot W, Kiavue N, et al.(2021) Efficacy of Circulating Tumor Cell Count-Driven vs Clinician-Driven First-line Therapy Choice in Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer: The STIC CTC Randomized Clinical Trial. JAMA Oncol. Jan 01 2021; 7(1): 34-41. PMID 33151266

Bidard FC, Peeters DJ, Fehm T, et al.(2014) Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol. Apr 2014; 15(4): 406-14. PMID 24636208

Bonneville R, Krook MA, Chen HZ, et al.(2020) Detection of Microsatellite Instability Biomarkers via Next-Generation Sequencing. Methods Mol Biol. 2020; 2055: 119-132. PMID 31502149

Burstein HJ, DeMichele A, Somerfield MR, et al.(2023) Testing for ESR1 Mutations to Guide Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update. J Clin Oncol. Jun 20 2023; 41(18): 3423-3425. PMID 37196213

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