NCCN VERSION 2 2015

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MS-4

NCCN Guidelines Index

Breast Cancer Table of Contents

Discussion

NCCN Guidelines Version 2.2015

Breast Cancer

Principles of HER2 Testing

Along with ER and PR, the determination of HER2 tumor status is

recommended for all newly diagnosed invasive breast cancers and for

first recurrences of breast cancer whenever possible. The NCCN Breast

Cancer Panel endorses CAP accreditation for anatomic pathology

laboratories performing HER2 testing.

HER2 status can be assessed by measuring the number of HER2 gene

copies using in situ hybridization [ISH] techniques, or by a

complementary method in which the quantity of HER2 cell surface

receptors is assessed by IHC.

Assignment of HER2 status based on

mRNA assays or multigene arrays is not recommended. The accuracy

of HER2 assays used in clinical practice is a major concern, and results

from several studies have shown that false-positive

19-22

as well as

false-negative

19,23

HER2 test results are common. A joint panel from

ASCO and CAP has issued updated HER2 testing guidelines to avoid

such false-positive or false-negative results. These updated guidelines

have been published in the

Archives of Pathology & Laboratory

Medicine

and ASCO's

Journal of Clinical Oncology.

24,25

The NCCN

Panel endorses these updated ASCO/CAP recommendations for quality

HER2 testing and have been outlined these recommendations in

Principles of HER2 Testing

HER2-Positive Result

Consistent with the ASCO/CAP guidelines, the NCCN Panel considers

either IHC or ISH with either a single or dual probe as acceptable

methods for making an initial determination of HER2 tumor status.

Breast cancer tumors are classified as HER2-positive if they are scored

as 3+ by an IHC method defined as uniform membrane staining for

HER2 in 10% or more of tumor cells or demonstrate HER2 gene

amplification by an ISH method (single probe, average

HER2

copy

number ≥6.0 signals/cell; dual probe

HER2/CEP17

ratio ≥2.0 with an

average HER2 copy number ≥4.0 signals/cell; dual probe

HER2/CEP17

ratio ≥2.0 with an average HER2 copy number <4.0 signals/cell;

HER2/CEP17

ratio <2.0 with an average HER2 copy number ≥6.0

signals/cell).

High average copy number of HER2 (

≥6.0 signals/cell) is considered

positive regardless of the

HER2/CEP17

ratio.

The rationale cited

by the

joint committee

for including rare scenarios such as HER2 positivity

when

dual probe

HER2/CEP17

ratio is ≥2.0 and average HER2 copy

number is <4.0 signals/cell is that

the first-generation trials of adjuvant

trastuzumab included a small number of patients with a

HER2

/CEP17 ratio ≥2.0 and an average HER2 copy number <4.0

signals/cell. There is no trend in these data, suggesting that these

patients were not responsive to trastuzumab and the trastuzumab

has a favorable safety profile.

Equivocal Result

The NCCN Panel agrees with the ASCO/CAP HER2 committee that

results of IHC are equivocal if scored as IHC 2+ “based on

circumferential membrane staining that is incomplete and/or

weak/moderate and within >10% of the invasive tumor cells or complete

and circumferential membrane staining that is intense and within ≤ 10%

of the invasive tumor cells.” In such cases, the panel recommends

reflex testing using the ISH method on the same specimen

repeating

tests if a new specimen is available.

Similarly, samples with equivocal results by an ISH assay (for example,

single probe ISH average

HER2

copy number ≥4.0 and <6.0

signals/cell; and dual probe

HER/CEP17

ratio <2.0 with an average

HER2 copy number ≥4.0 signals/cell) must be confirmed by reflex