Download 2.04.76 - Premera Blue Cross

MEDICAL POLICY
POLICY
RELATED POLICIES
POLICY GUIDELINES
DESCRIPTION
SCOPE
BENEFIT APPLICATION
RATIONALE
REFERENCES
CODING
APPENDIX
HISTORY
Quantitative Assay for Measurement of HER2 Total
Protein Expression and HER2 Dimers
Number
Effective Date
Revision Date(s)
Replaces
2.04.76
February 9, 2016
02/09/16; 12/08/15; 12/7/14; 12/09/13; 12/19/12;12/13/11
N/A
Policy
[TOP]
The assessment of HER2 status by quantitative total HER2 protein expression and HER2 homodimer
measurement is considered investigational.
Related Policies
[TOP]
5.01.514
Trastuzumab and Other HER2 Inhibitors
Policy Guidelines
[TOP]
Coding
CPT
84999
Unlisted Chemistry procedure
Description
[TOP]
Novel assays that quantitatively measure total human epidermal growth factor receptor 2 (HER2) protein
expression and homodimers have been developed to improve the accuracy and consistency of HER2 testing.
The evidence for assessment of HER2 status using quantitative total HER2 protein expression and HER2
homodimer measurement in patients who have breast cancer and are undergoing assessment of HER2 status
includes validation studies and retrospective analysis of association between levels and survival outcomes.
Relevant outcomes are overall survival, disease-specific survival, test accuracy, and test validity. Retrospective
analysis using HERmark® have shown that the assay may predict a worse response to trastuzumab in certain
populations. However, findings have been inconsistent, and no clear association with clinical outcomes has been
shown. Additionally, cut points for defining patient groups varied across studies. Clinical utility of the HERmark®
assay has not been demonstrated, and clinical trials are needed to determine the impact on clinical outcomes of
patients stratified by the HERmark® assay. The evidence is insufficient to determine the effects of the technology
on health outcomes.
Background
The HER family of receptor tyrosine kinases (EGFR/HER1, ErbB2/HER2, ErbB3/HER3, ErbB4/HER4) plays a
major role in the pathogenesis of many solid tumors. In approximately 25% to 30% of breast cancers,
overexpression of HER2 has been linked to shorter disease-free (DFS) and overall survival (OS), lack of
responsiveness to tamoxifen antiestrogen therapy, and altered responsiveness to a variety of cytotoxic
chemotherapy regimens.
Trastuzumab, a monoclonal antibody directed at the extracellular domain of HER2 has offered significant DFS
and OS advantages in the metastatic and adjuvant settings in HER2-overexpressing patients, although not all
patients respond. Fewer than 50% of patients with metastatic HER2-positive breast cancer show initial benefit
from trastuzumab treatment, and many of those eventually develop resistance. (1)
Current methodologies for the selection of HER2-positive patients include immunohistochemistry (IHC) to detect
HER2 protein overexpression, and fluorescence in situ hybridization (FISH) to detect HER2 gene amplification.
However, controversy still exists regarding the accuracy, reliability, and interobserver variability of these assay
methods. IHC provides a semiquantitative measure of protein levels (scored as 0, 1+, 2+, 3+) and the
interpretation may be subjective. FISH is a quantitative measurement of gene amplification, in which the HER2
gene copy number is counted. However, FISH, which is considered to be more quantitative analytically, is not
always representative of protein expression, and multiple studies have failed to demonstrate a relationship
between HER2 gene copy number and response to trastuzumab. Whereas patients who overexpress HER2
protein (IHC) or show evidence of HER2 gene amplification (FISH) have been shown to experience better
outcomes on trastuzumab than those scored negative by those assays, differences in the degree of expression or
amplification by these methods have generally not been shown to discriminate between groups with different
outcomes. IHC and FISH testing may be affected by interlaboratory variability, and neither test provides
quantitative data that reflect the activation state of signaling pathways in tumors, which may limit their utility in
patient selection. (2) Most laboratories in North America and Europe use IHC to determine HER2 protein status,
with equivocal category results (2+) confirmed by FISH (or more recently by chromogenic in situ hybridization
[CISH]).
Normally, HER2 activates signaling pathways by dimerizing with ligand-bound EGFR-family members such as
HER1 and HER3. A HER2 ligand has not been identified, but overexpressed HER2 is constitutively active. When
HER2 is pathologically overexpressed, the receptor may homodimerize and activate signaling cascades in the
absence of the normal regulatory control imposed by the requirement for ligand binding of its heterodimerization
partners.
A novel assay (HERmark® Breast Cancer Assay; Monogram Biosciences, South San Francisco, CA) was
developed to quantify total HER2 protein expression (H2T) and HER2 homodimers (H2D) in formalin-fixed,
paraffin-embedded (FFPE) tissue samples.
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratorydeveloped tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Act
(CLIA). HERmark® is available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by
CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any
regulatory review of this test.
Scope
[TOP]
Medical policies are systematically developed guidelines that serve as a resource for Company staff when
determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject
to the limits and conditions of the member benefit plan. Members and their providers should consult the member
benefit booklet or contact a customer service representative to determine whether there are any benefit limitations
applicable to this service or supply. This medical policy does not apply to Medicare Advantage.
Benefit Application
[TOP]
N/A
Rationale
[TOP]
Populations
Individuals:
 With breast
cancer who are
undergoing
assessment of
HER2 status
Interventions
Interventions of interest
are:
 Assessment of HER2
status using quantitative
total HER2 protein
expression and HER2
homodimer
measurement
Comparators
Comparators of interest
are:
 Assessment of HER2
status using
immunohistochemistry
or fluorescence in situ
hybridization
Outcomes
Relevant outcomes
include:
 Overall survival
 Disease-specific
survival
 Test accuracy
 Test validity
This policy was created in 2011 with the most recent MEDLINE literature search performed through November
12, 2015.
Validation of biomarker assessment to improve treatment outcomes is a multistep process. In general, important
steps in the validation process address the following:
 Analytic validity: measures technical performance, i.e., whether the test accurately and reproducibly
detects the biomarker of interest.
 Clinical validity: measures the strength of the associations between the selected biomarkers and clinical
status.
 Clinical utility: determines whether the use of specific biomarker assessments to guide treatment
decisions improves patient outcomes such as survival or adverse event rate compared with standard
treatment without genotyping.
Analytic Validity
The HERmark® assay uses a proprietary, proximity-based platform (proximity ligation assay) to measure total
HER2 protein expression (H2T) and HER2 homodimers (H2D). Antibody binding to HER2 and other HER proteins
releases fluorescent reporter tags (VeraTag™, Monogram Biosciences). Proximity of a bound HER2 antibody to a
different bound HER antibody indicates a HER2 protein (H2T); proximity of 2 bound HER2 antibodies indicates a
HER2 homodimer (H2D). Quantification of fluorescence permits quantification of H2T and H2D.
The HERmark® assay is currently commercially available only for quantification of H2T and H2D in breast cancer.
The company plans to validate use of the HERmark® test to measure HER heterodimers. The company website
indicates that assays currently are available for HER2:HER1 and HER2:HER3 heterodimers; these apparently are
for use in drug development. (3)
HER2 protein quantification was normalized to tumor area and compared with receptor numbers in 12 human
tumor cell lines (determined by fluorescence-activated cell sorting and standard immunohistochemistry [IHC]) and
to IHC categories in 170 human breast tumors. (2) In contrast to conventional IHC test categories, HER2 protein
levels determined by the VeraTag™ assay represent a continuous measurement over a dynamic range greater
than 2 log10, and HER2 homodimer levels were consistent with crosslinking and immunoprecipitation results.
Huang et al. (2010) compared results of the HERmark® assay with those of IHC and fluorescence in situ
hybridization (FISH) centrally performed at the Mayo Clinic in 237 archived formalin-fixed, paraffin-embedded
(FFPE) breast cancers. (4) IHC had already been performed at the time of initial diagnosis in all of the cases but
was repeated for the purpose of this validation, and interpreted by one reviewer and scored as negative,
equivocal, or positive according to the American Society of Clinical Oncologists/College of American Pathologists
guidelines. (5) Reflex FISH for HER2 gene amplification also had been performed at the time of initial diagnosis
on all 94 of the IHC 2+ cases. Repeat FISH was performed at the same laboratory and an overall evaluation
performed by one pathologist. Of the 84 cases in the immunohistochemically negative subgroup, 80 (95%), 2
(2%), and 2 (2%) were classified as negative, equivocal, and positive by HERmark®, respectively. Of the 101
cases in the immunohistochemically equivocal subgroup, 33 (32.7%), 31 (30.7%), and 37 (36.6%) were classified
as negative, equivocal, and positive by HERmark®, respectively. Of the 52 cases in the immunohistochemically
positive subgroup, 1 (2%), 3 (6%), and 48 (92%) were classified as negative, equivocal, and positive by
HERmark®, respectively. Overall concordance was 67%, with a weighted κ of 63% (95% confidence interval [CI],
55% to 70%). When equivocal cases were excluded from the HERmark® and IHC results, positive and negative
concordance between HERmark® and central immunohistochemical testing was 98%, and overall concordance
was 98%, with a κ of 95% (95% CI: 89% to 100%).
Reflex FISH was performed on 94 breast cancers that had been determined as 2+ immunohistochemically at the
time of initial diagnosis. Variable H2T and H2D levels were correlated with corresponding results for the
HER2/centromeric probe for chromosome 17 (HER2/CEP17) ratio. Of 94 cases that were 2+
immunohistochemically, 62 (66%), 5 (5%), and 27 (29%) were determined at the same central laboratory as
negative (<10.5), equivocal (10.5 ≤H2T≤17.8), and positive (>17.8) by FISH, respectively. (Units of H2T
measurement are relative fluorescence [defined as relative peak area x illumination buffer volume] per mm2 of
invasive tumor [RF/mm2].) Of 62 FISH-negative cases, 24 (39%), 21 (34%), and 17 (27%) were determined as
negative, equivocal, and positive by HERmark®, respectively. Of 5 FISH-equivocal cases, 1 (20%), 2 (40%), and
2 (40%) were determined as negative, equivocal, and positive by HERmark®, respectively. Of 27 FISH-positive
cases, 3 (11%), 6 (22%), and 18 (67%) were determined as negative, equivocal, and positive by HERmark®,
respectively.
Clinical Validity
Bates et al. (2011) measured H2T in FFPE primary breast tumors from 98 women treated with trastuzumabbased therapy for metastatic breast cancer. (6) Using subpopulation treatment effect pattern plots, the population
was divided into H2T low (H2T <13.8), H2T high (H2T ≥68.5), and H2T intermediate (13.8 ≤H2T<68.5)
subgroups. Kaplan-Meier analyses were used to compare groups for time-to-progression (TTP) and overall
survival (OS). Cox multivariate analyses were used to identify correlates of clinical outcome. Bootstrapping
analyses were used to test robustness of results. TTP improved with increasing H2T until, at the highest levels of
H2T, an abrupt decrease in the TTP was observed. Kaplan-Meier analyses demonstrated that patients with H2T
low tumors (median TTP, 4.2 months; hazard ratio [HR], 3.7; p<0.001) or H2T high tumors (median TTP, 4.6
months; HR=2.7; p=0.008) had significantly shorter TTP than patients whose tumors were H2T intermediate
(median TTP, 12 months). OS analyses yielded similar results. The authors concluded that patients with high
levels of H2T may represent a subgroup with de novo resistance to trastuzumab but that these results were
preliminary and required confirmation in larger controlled clinical cohorts.
Joensuu et al. (2011) reported results of measurement of H2T using HERmark® from formalin-fixed tumor tissue
of 899 women (89%) who participated in the FinHer trial (ISRCTN76560285) to determine if very high tumor H2T
content influences outcome in early breast cancer treated with adjuvant trastuzumab plus chemotherapy. (7) In a
chromogenic in situ hybridization (CISH) test, 197 patients (21.9%) had HER2-positive cancer and were randomly
assigned to receive trastuzumab or control. Tumor H2T levels varied greatly, by 1,808-fold. High H2T levels
strongly correlated with a positive HER2 status by CISH (P<0.001). Patients with very high H2T (defined by ≥22fold the median of HER2-negative cancers [5.7; range, 0.4-118.4]; 13% of CISH-positive cancers) did not benefit
from adjuvant trastuzumab (HR for distant recurrence, 1.23; 95% CI: 0.33 to 4.62; p=0.75), whereas the
remaining patients with HER2-positive disease by CISH (87%) did benefit (HR for distant recurrence, 0.52; 95%
CI: 0.28 to 1.00; p=0.050). The authors concluded that patients with HER2-positive breast cancer with very high
tumor HER2 content may benefit less from adjuvant trastuzumab compared with those whose cancer has more
moderate HER2 content.
Toi et al. (2010) investigated the relationship between H2T or H2D and OS in 72 patients drawn from 6 oncology
clinics in Japan who had metastatic breast cancer and had been treated with at least one chemotherapy regimen
before receiving trastuzumab. (8) Patients were originally selected for treatment with trastuzumab by IHC (88%)
or FISH (12%). HERmark® assay results were correlated with OS using univariate Kaplan-Meier, hazard function
plots, and multivariate Cox regression analyses. Clinical outcome data were drawn from medical chart review.
Measurements of H2T and H2D were tested for association with OS, defined as the time from start of
trastuzumab treatment to cancer-associated death or end of follow-up (median, 18.2 months). Median duration of
trastuzumab treatment was 14.6 months. Overall 2-year survival was 60.8% (95% CI: 48.4% to 73.2%). In
univariate analyses, patients were classified into 4 subgroups defined by the 25th, 50th, and 75th percentiles for
each of the 3 variables, H2T, H2D, and their ratio, H2D/ H2T. Hazard function plots were estimated in the 4 H2T
sub-groups, and sub-groups with the 25% highest and lowest H2T values had substantially lower risk of death
than the middle 2 subgroups. Dividing the cohort into high HER2-expressing (≥the median value of H2T) and low
HER2-expressing (<the median value of H2T) sub-groups and using Cox regression with the continuous H2T
value in each of sub-group, patients with higher HER2 values had longer survival than those with lower H2T
values in the high HER2- expressing group (HR=0.06; p=0.010; 95% CI: 0.01-0.51). In contrast, in the low HER2expressing group, the opposite trend (those with lower H2T values were favored) was observed (HR: 16.0;
p=0.017; 95% CI: 1.64-155.9). The authors concluded that there are 2 subpopulations of patients in this cohort
that behave differently with respect to HER2 expression and OS and that the quantitative amount of HER2
expression measured by HERmark® may be a useful new marker to identify a more relevant target population for
trastuzumab treatment in patients with metastatic breast cancer.
Lipton et al. (2010) used the HERmark® assay to quantify HER2 expression and examined outcomes in 102
trastuzumab-treated metastatic breast cancer patients previously assessed as IHC 3+ by local but not central
IHC, or FISH-positive, and then retested by central FISH. (9) Of 102 metastatic breast cancer patients previously
scored as IHC 3+ or 2+/FISH-positive and treated with trastuzumab-containing regimens, 98 had both central
FISH and H2T values. Sixty-six (87%) of 76 central FISH-positive patients had high H2T levels (concordant
positive), and 19 (86%) of 22 central FISH-negative patients were H2T low (concordant negative). Three (14%) of
22 central FISH-negative patients were H2T high (discordant H2T high), and 10 (13%) of 76 central FISH-positive
patients were H2T low (discordant H2T low). The concordant positive group had a significantly longer TTP
(median, 11.3 months) compared with the concordant negative group (median, 4.5 months; HR=0.42; p<0.001),
and also compared with the discordant H2T low group (median, 3.7 months; HR=0.43; p=0.01). The discordant
H2T low group behaved similarly compared with concordant negatives (HR=1; p=0.99). In analyses restricted to
central FISH-positive patients only (n=77), Cox proportional hazards multivariate regression identified H2T as an
independent predictor of TTP (HR=0.29; p<0.001) and OS (HR =0.19, p< 0.001). The authors concluded that a
subset of patients with HER2 gene amplification by FISH express low levels of HER2 protein and have reduced
response to trastuzumab-containing therapy, similar to FISH-negative.
In a subsequent retrospective analysis of this cohort, Lipton et al. (2013) examined progression-free survival
(PFS) and OS in subgroups defined by expression of HER3 (H3T) and p95HER2 (p95), a truncated form of HER2
that does not bind trastuzumab and is a marker of trastuzumab resistance. (10) HER3 and p95 were quantified
using VeraTag™ platforms. Results of H3T analysis were available from 89 patients; of these, 61 (69%) were
H2T-high (>13.8). Within this group, median PFS was 12.1 months in patients with low H3T (≤3.5) and 5.0 months
in patients with high H3T (>3.5; HR=2.7; p=0.002). Median PFS in patients with low H2T (<13.8) was 4.2 months.
No significant difference in OS was observed among any groups. In exploratory analysis using regression tree
analysis (recursive partitioning), the first split of the tree was based on a H2T cutoff of 16.1, separating patients
with low HER2 expression (H2T <16.1) from those with high HER2 expression (H2T ≥16.1). Patients were next
segregated by intermediate HER2 expression (16.1 ≤ H2T ≤ 68.3) versus very high HER2 expression (H2T >
68.3). H2T cutoffs of 16.1 and 68.3 to define low, intermediate, and high groups were found to have greater
discrimination. Median PFS (15.7 months) and OS (47.6 months) were longest in the subgroup characterized as
H2T-intermediate (16.1 ≤H2T≤68.3), H3T-low (≤3.89), and p95 low (≤3.75), compared with other groups (median
PFS range, 4.0-7.8 months; median OS range, 23-27 months). In the entire group of HER2-positive, trastuzumabtreated patients, low (normal) H2T (≤16.1) and very high H2T (>68.3) were correlated with shorter PFS and OS. A
subsequent study that used VeraTag™ to quantify p95HER2 found significantly shorter PFS and OS among H2Tpositive, hormone receptor-positive, trastuzumab-treated patients with high p95, using a different cutoff of 2.8.11
This association was not found among hormone receptor-negative patients.
Han et al. (2012) performed a similar retrospective analysis in 52 women with locally advanced or metastatic
HER2-positive (3+ on IHC or gene amplification by FISH) breast cancer that had progressed after treatment with
an anthracycline, a taxane, and trastuzumab. (12) Patients were treated with lapatinib and capecitabine until
disease progression or intolerance. Among all patients, median TTP was longer in patients with high H2T (>13.8;
5.0 months) than in patients with low H2T (<13.8; 1.8 months; p=0.047). However, a cutoff of 14.95 had greater
discrimination (lower chi-square p-value). Results were similar using this cutoff; median TTP in patients with high
H2T (>14.95) was 5.2 months and in those with low H2T (<14.95), 1.8 months (p=0.018). No significant
association was found between H2T levels and OS using either cut point. Among subgroups defined by H3T
levels, median TTP was significantly longer (5.6 months) in patients with both high H2T (>14.95) and high H3T
(>0.605) than in other groups (2.2 months; p=0.002).
Duchnowska et al. (2012) investigated the correlation between H2T in primary breast cancers and time-to-brain
metastasis (TTBM) in HER2+ advanced breast cancer patients treated with trastuzumab. (13) The patient sample
included 142 consecutive patients who were administered trastuzumab-based therapy for HER2+ metastatic
breast cancer. HER2/neu gene copy number was quantified as the HER2/CEP17 ratio by central laboratory FISH.
HER2 protein was quantified as H2T by the HERmark® assay in FFPE tumor samples. HER2 variables were
correlated with clinical features, and TTBM was measured from the initiation of trastuzumab-containing therapy. A
higher H2T level (continuous variable) was correlated with shorter TTBM, whereas HER2 amplification by FISH
and a continuous HER2/CEP17 ratio were not predictive (p =0.013, 0.28, and 0.25, respectively). In the subset of
patients that was centrally determined by FISH to be HER2+, an above-the-median H2T level (>58) was
significantly associated with a shorter TTBM (HR=2.4. p=0.005), whereas this was not true for the median
HER2/CEP17 ratio by FISH (p=0.4). Correlation between a continuous H2T level and TTBM was confirmed on
multivariate analysis (HR=3.3, p=0.024). The authors concluded that their data revealed a strong relationship
between quantitative HER2 protein expression level and risk for brain relapse in HER2+ advanced breast cancer
patients and that quantitative assessment of HER2 protein expression may inform and facilitate refinements in
therapeutic treatment strategies for selected subpopulations of patients in this group.
Barros et al. (2014) used proximity ligation assays to characterize specific HER2 heterodimers and their
association with breast-cancer specific survival (BCSS) and disease-free interval (DFI). (14) Tumor samples were
from patients who had primary operable, invasive breast cancer at a single center in England. Among 1858
unselected patients, high levels of all 3 HER2 heterodimers (HER2/HER1 [EGFR], HER2/HER3, HER2/HER4)
showed statistically worse BCSS and DFI compared with low levels (range of HRs for BCSS, 0.62-0.66 [95% CIs,
0.45 to 0.92]; p values ≤0.014; range of HRs for DFI, 0.64-0.72 [95% CIs, 0.47 to 0.98]; p values ≤0.037). Cut
points were determined using X-tile, a graphical method that has been used in breast cancer research. (15)
However, among the subgroup of 224 patients who were HER2-positive by IHC/FISH, associations between
HER2 heterodimers and patient outcomes were not statistically significant, regardless of trastuzumab therapy. In
a follow-up study, Green et al. (2014) showed that HER2/HER3 heterodimers were significantly associated with
shorter BCSS among unselected estrogen receptor-positive patients, but not among estrogen receptor-negative
patients.16 Among the subset of HER2-positive patients, there was no association between HER2/HER3
heterodimers and BCSS in estrogen receptor-positive or -negative patients who had or had not received
trastuzumab.
Section Summary
Retrospective studies report an association between H2T levels and survival outcomes. However, for these
analyses, different cut points are used and results are variable (see Table 1).
Table 1. Summary of studies of HERMark® Clinical Validity
Reference
Bates (2011)
Joensuu
7
(2011)
Toi (2010)
8
6
Cutoffs Used
Low
High
<13.8
>68.5
Result
a
NA
≥125.4
<median
b
H2T
≥median
b
H2T
Group with intermediate H2T levels
experienced longest TTP and OS
Patients with HER2-positive breast
cancer with very high tumor HER2
content may benefit less from adjuvant
trastuzumab than those whose cancer
has more moderate HER2 content
 Patients with higher H2T values
(>75%ile) lived longer than those with
lower H2T values in the high HER2expressing group
 Patients with lower H2T values live
longer than those with higher H2T
values in the low HER2-expressing
Favored Group
Low
Intermediate



High


Lipton
9
(2010)
<13.8
>68.5
Lipton
10
(2013)
12
Han (2012)
<16.1
>68.3
<13.8
≥13.8
Duchnowska
13
(2012)
<58
Barros
14
(2014)
c
≥58
c
Per specific heterodimer
studied
group
Better response to trastuzumab at
higher levels of HER2 total expression
observed
Low H2T and high H2T correlated with
shorter PFS and OS
TTP was longer in patients with high
H2T than in patients with low H2T
Correlation between a continuous H2T
level and TTBM was confirmed on
multivariate analysis
Low heterodimer levels favored among
unselected patients; no association
observed among trastuzumab-treated
or -naive HER2-positive patients







CISH: chromogenic in situ hybridization; H2T: HER2 protein; NA: not applicable; OS: overall survival; PFS: progression-free survival; TTBM:
time to brain metastasis; TTP: time to progression.
a
Cutoff for very high H2T (≥22-fold the median H2T of cancers HER2-negative by CISH. [5.7])
b
Absolute values not reported. c Median H2T level. H2T value of 50 was a better discriminator (smaller p value in Cox models).
Clinical Utility
Data on the clinical utility of HERmark® are lacking. Clinical trials are needed to understand the relationship
between quantitative HER2 expression and homodimer measurements with clinical outcomes in breast cancer
patients stratified by the HERmark® assay receiving anti-HER2 therapy in the adjuvant and metastatic settings.
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in October 2015 did not identify any ongoing or unpublished trials that would likely
influence this review.
Summary of Evidence
The evidence for assessment of HER2 status using quantitative total human epidermal growth factor receptor 2
(HER2) protein expression and HER2 homodimer measurement in patients who have breast cancer and are
undergoing assessment of HER2 status includes validation studies and retrospective analysis of association
between levels and survival outcomes. Relevant outcomes are overall survival, disease-specific survival, test
accuracy, and test validity. Retrospective analysis using HERmark® have shown that the assay may predict a
worse response to trastuzumab in certain populations. However, findings have been inconsistent, and no clear
association with clinical outcomes has been shown. Additionally, cut points for defining patient groups varied
across studies. Clinical utility of the HERmark® assay has not been demonstrated, and clinical trials are needed
to determine the impact on clinical outcomes of patients stratified by the HERmark® assay. The evidence is
insufficient to determine the effects of the technology on health outcomes.
Practice Guidelines and Position Statements
NCCN Guidelines on the treatment of breast cancer (version 3.2015) do not address the use of HERmark®. (17)
U.S. Preventive Services Task Force Recommendations
Not applicable.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the
discretion of local Medicare carriers.
Palmetto GBA determines coverage and reimbursement for laboratories that perform molecular diagnostic testing
and submit claims to Medicare in Medicare Jurisdiction E (California, Nevada, Hawaii). Palmetto GBA’s decisions
apply for all molecular diagnostic tests for Medicare.
Palmetto GBA has completed an assessment of HERmark® and determined that the test meets criteria for
analytic and clinical validity, and clinical utility as a reasonable and necessary Medicare benefit.18 Effective
December 9, 2011, Palmetto GBA will reimburse HERmark® services for patients with breast cancer.
References
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1. DeFazio-Eli L, Strommen K, Dao-Pick T, et al. Quantitative assays for the measurement of HER1-HER2
heterodimerization and phosphorylation in cell lines and breast tumors: applications for diagnostics and
targeted drug mechanism of action. Breast Cancer Res. 2011;13(2):R44. PMID 21496232
2. Shi Y, Huang W, Tan Y, et al. A novel proximity assay for the detection of proteins and protein
complexes: quantitation of HER1 and HER2 total protein expression and homodimerization in formalinfixed, paraffin-embedded cell lines and breast cancer tissue. Diagn Mol Pathol. 2009;18(1):11-21.
3. Monogram biosciences announces HER2:HER3 heterodimer and HER3/PI3K VeraTag™ assays are
now available for use in development of cancer therapeutics: November 11, 2008.
http://www.businesswire.com/news/home/20081111005841/en/Monogram-Biosciences-AnnouncesHER2HER3-Heterodimer-HER3PI3K-VeraTag. Accessed January 14, 2016.
4. Huang W, Reinholz M, Weidler J, et al. Comparison of central HER2 testing with quantitative total HER2
expression and HER2 homodimer measurements using a novel proximity-based assay. Am J Clin
Pathol. 2010;134(2):303-311.
5. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American
Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast
cancer. Arch Pathol Lab Med. 2007;131(1):18-43.
6. Bates M, Sperinde J, Köstler WJ, et al. Identification of a subpopulation of metastatic breast cancer
patients with very high HER2 expression levels and possible resistance to trastuzumab. Ann Oncol.
2011;22(9):2014-2020.
7. Joensuu H, Sperinde J, Leinonen M, et al. Very high quantitative tumor HER2 content and outcome in
early breast cancer. Ann Oncol. 2011;22(9):2007-2013.
8. Toi M, Sperinde J, Huang W, et al. Differential survival following trastuzumab treatment based on
quantitative HER2 expression and HER2 homodimers in a clinic-based cohort of patients with metastatic
breast cancer. BMC Cancer. 2010;10:56. PMID 20178580
9. Lipton A, Köstler WJ, Leitzel K, et al. Quantitative HER2 protein levels predict outcome in fluorescence in
situ hybridization-positive patients with metastatic breast cancer treated with trastuzumab. Cancer.
2010;116(22):5168-5178.
10. Lipton A, Goodman L, Leitzel K, et al. HER3, p95HER2, and HER2 protein expression levels define
multiple subtypes of HER2-positive metastatic breast cancer. Breast Cancer Res Treat. Aug 20 2013.
PMID 23959396
11. Duchnowska R, Sperinde J, Chenna A, et al. Quantitative measurements of tumoral p95HER2 protein
expression in metastatic breast cancer patients treated with trastuzumab: independent validation of the
p95HER2 clinical cutoff. Clin Cancer Res. May 15 2014;20(10):2805-2813. PMID 24668646
12. Han SW, Cha Y, Paquet A, et al. Correlation of HER2, p95HER2 and HER3 expression and treatment
outcome of lapatinib plus capecitabine in her2-positive metastatic breast cancer. PLoS One.
2012;7(7):e39943. PMID 22848366
13. Duchnowska R, Biernat W, Szostakiewicz B, et al. Correlation between quantitative HER-2 protein
expression and risk for brain metastases in HER-2+ advanced breast cancer patients receiving
trastuzumab-containing therapy. Oncologist. 2012;17(1):26-35. PMID 22234627
14. Barros FF, Abdel-Fatah TM, Moseley P, et al. Characterisation of HER heterodimers in breast cancer
using in situ proximity ligation assay. Breast Cancer Res Treat. Apr 2014;144(2):273-285. PMID
24557338
15. Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for biomarker assessment and
outcome-based cut-point optimization. Clin Cancer Res. Nov 1 2004;10(21):7252-7259. PMID 15534099
16. Green AR, Barros FF, Abdel-Fatah TM, et al. HER2/HER3 heterodimers and p21 expression are capable
of predicting adjuvant trastuzumab response in HER2+ breast cancer. Breast Cancer Res Treat. May
2014;145(1):33-44. PMID 24706169
17. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: breast
cancer, version 3.2015. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed
January 14, 2016.
18. Palmetto GBA®. MolDX: HERmark assay by Monogram coding and billing guidelines (M00028), last
update 06/05/2014.
http://www.palmettogba.com/palmetto/MolDX.nsf/DocsCat/MolDx%20Website~MolDx~Browse%20By%2
0Topic~Covered%20Tests~8TVSBJ3016?open&navmenu=Browse%5EBy%5ETopic%7C%7C%7C%7C
. Accessed January 14, 2016.
19. Blue Cross Blue Shield Association. Medical Policy Reference Manual. Quantitative Assay for
Measurement of HER2 Total Protein Expression and HER2 Dimers. Policy no. 2.04.76, 2015.
Coding
[TOP]
Codes
CPT
Number
84999
Description
Unlisted chemistry procedure
Appendix
[TOP]
N/A
History
[TOP]
Date
12/13/11
12/19/12
12/09/13
12/17/14
12/08/15
02/09/16
Reason
New Policy – Add to Pathology/Laboratory Section. Policy created with literature search through
September 2011; considered investigational.
Replace policy. Rationale updated based on a literature search through September 2012.
Reference 9 added. Other references renumbered. Policy statement unchanged. Updated title in
related policy 5.01.514 to include: “Other”.
Replace policy. Policy updated with a literature search through July 2013; references 3, 11, and 12
added. No change in policy statement. Reference 14 updated.
Annual Review. Policy updated with literature review through September 17, 2014; references 11,
14-16, and 18 added; references 3 and 17 updated. No change to policy statement.
Annual Review. Policy reviewed. References unchanged. Policy statement unchanged.
Annual Review. Policy updated with literature review through November 12, 2015; no references
added; references 3 and 17 updated. No change to policy statement.
Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts
policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical
technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in
their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific
medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).
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‫( فارسی‬Farsi):
‫اين اعالميه ممکن است حاوی اطالعات مھم درباره فرم‬. ‫اين اعالميه حاوی اطالعات مھم ميباشد‬
‫ به تاريخ ھای مھم در‬.‫ باشد‬Premera Blue Cross ‫تقاضا و يا پوشش بيمه ای شما از طريق‬
‫شما ممکن است برای حقظ پوشش بيمه تان يا کمک در پرداخت ھزينه‬. ‫اين اعالميه توجه نماييد‬
‫شما حق‬. ‫ به تاريخ ھای مشخصی برای انجام کارھای خاصی احتياج داشته باشيد‬،‫ھای درمانی تان‬
‫ برای کسب‬.‫اين را داريد که اين اطالعات و کمک را به زبان خود به طور رايگان دريافت نماييد‬
‫( تماس‬800-842-5357 ‫ تماس باشماره‬TTY ‫ )کاربران‬800-722-1471 ‫اطالعات با شماره‬
.‫برقرار نماييد‬
Polskie (Polish):
To ogłoszenie może zawierać ważne informacje. To ogłoszenie może
zawierać ważne informacje odnośnie Państwa wniosku lub zakresu
świadczeń poprzez Premera Blue Cross. Prosimy zwrócic uwagę na
kluczowe daty, które mogą być zawarte w tym ogłoszeniu aby nie
przekroczyć terminów w przypadku utrzymania polisy ubezpieczeniowej lub
pomocy związanej z kosztami. Macie Państwo prawo do bezpłatnej
informacji we własnym języku. Zadzwońcie pod 800-722-1471
(TTY: 800-842-5357).
Português (Portuguese):
Este aviso contém informações importantes. Este aviso poderá conter
informações importantes a respeito de sua aplicação ou cobertura por meio
do Premera Blue Cross. Poderão existir datas importantes neste aviso.
Talvez seja necessário que você tome providências dentro de
determinados prazos para manter sua cobertura de saúde ou ajuda de
custos. Você tem o direito de obter esta informação e ajuda em seu idioma
e sem custos. Ligue para 800-722-1471 (TTY: 800-842-5357).
Fa’asamoa (Samoan):
Atonu ua iai i lenei fa’asilasilaga ni fa’amatalaga e sili ona taua e tatau
ona e malamalama i ai. O lenei fa’asilasilaga o se fesoasoani e fa’amatala
atili i ai i le tulaga o le polokalame, Premera Blue Cross, ua e tau fia maua
atu i ai. Fa’amolemole, ia e iloilo fa’alelei i aso fa’apitoa olo’o iai i lenei
fa’asilasilaga taua. Masalo o le’a iai ni feau e tatau ona e faia ao le’i aulia le
aso ua ta’ua i lenei fa’asilasilaga ina ia e iai pea ma maua fesoasoani mai ai
i le polokalame a le Malo olo’o e iai i ai. Olo’o iai iate oe le aia tatau e maua
atu i lenei fa’asilasilaga ma lenei fa’matalaga i legagana e te malamalama i
ai aunoa ma se togiga tupe. Vili atu i le telefoni 800-722-1471
(TTY: 800-842-5357).
Español (Spanish):
Este Aviso contiene información importante. Es posible que este aviso
contenga información importante acerca de su solicitud o cobertura a
través de Premera Blue Cross. Es posible que haya fechas clave en este
aviso. Es posible que deba tomar alguna medida antes de determinadas
fechas para mantener su cobertura médica o ayuda con los costos. Usted
tiene derecho a recibir esta información y ayuda en su idioma sin costo
alguno. Llame al 800-722-1471 (TTY: 800-842-5357).
Tagalog (Tagalog):
Ang Paunawa na ito ay naglalaman ng mahalagang impormasyon. Ang
paunawa na ito ay maaaring naglalaman ng mahalagang impormasyon
tungkol sa iyong aplikasyon o pagsakop sa pamamagitan ng Premera Blue
Cross. Maaaring may mga mahalagang petsa dito sa paunawa. Maaring
mangailangan ka na magsagawa ng hakbang sa ilang mga itinakdang
panahon upang mapanatili ang iyong pagsakop sa kalusugan o tulong na
walang gastos. May karapatan ka na makakuha ng ganitong impormasyon
at tulong sa iyong wika ng walang gastos. Tumawag sa 800-722-1471
(TTY: 800-842-5357).
ไทย (Thai):
ประกาศนี ้มีข้อมูลสําคัญ ประกาศนี ้อาจมีข้อมูลที่สําคัญเกี่ยวกับการการสมัครหรื อขอบเขตประกัน
สุขภาพของคุณผ่าน Premera Blue Cross และอาจมีกําหนดการในประกาศนี ้ คุณอาจจะต้ อง
ดําเนินการภายในกําหนดระยะเวลาที่แน่นอนเพื่อจะรักษาการประกันสุขภาพของคุณหรื อการช่วยเหลือที่
มีค่าใช้ จ่าย คุณมีสิทธิที่จะได้ รับข้ อมูลและความช่วยเหลือนี ้ในภาษาของคุณโดยไม่มีค่าใช้ จ่าย โทร
800-722-1471 (TTY: 800-842-5357)
Український (Ukrainian):
Це повідомлення містить важливу інформацію. Це повідомлення
може містити важливу інформацію про Ваше звернення щодо
страхувального покриття через Premera Blue Cross. Зверніть увагу на
ключові дати, які можуть бути вказані у цьому повідомленні. Існує
імовірність того, що Вам треба буде здійснити певні кроки у конкретні
кінцеві строки для того, щоб зберегти Ваше медичне страхування або
отримати фінансову допомогу. У Вас є право на отримання цієї
інформації та допомоги безкоштовно на Вашій рідній мові. Дзвоніть за
номером телефону 800-722-1471 (TTY: 800-842-5357).
Tiếng Việt (Vietnamese):
Thông báo này cung cấp thông tin quan trọng. Thông báo này có thông
tin quan trọng về đơn xin tham gia hoặc hợp đồng bảo hiểm của quý vị qua
chương trình Premera Blue Cross. Xin xem ngày quan trọng trong thông
báo này. Quý vị có thể phải thực hiện theo thông báo đúng trong thời hạn
để duy trì bảo hiểm sức khỏe hoặc được trợ giúp thêm về chi phí. Quý vị có
quyền được biết thông tin này và được trợ giúp bằng ngôn ngữ của mình
miễn phí. Xin gọi số 800-722-1471 (TTY: 800-842-5357).