Biology Reference
In-Depth Information
for these patients
[14-17]
. Amplification of the gene for HER2, detected by fluorescence
in situ
hybridization (FISH) occurs in approximately the same proportion
[18]
. Trastuzumab
/
Herceptin is a recombinant humanized mAb that targets HER2 protein and prevents down-
stream signaling of this pathway
[18]
. Treatment with trastuzumab as monotherapy leads
to responses in 15-35% of patients with the response rate increasing to 50-70% when it is
administered with chemotherapy to patients with increased expression or amplification of
HER2 in their tumors, termed HER2+
[19-23]
. The pivotal trial for this drug in combina-
tion with chemotherapy enrolled 469 patients with previously untreated, HER2+, metastatic
breast cancer
[18]
. A central laboratory reviewed the tumor samples to quantify the level
of HER2 overexpression using IHC staining, which is scored semi-quantitatively as 2+ for
weak to moderate staining of the entire tumor cell membrane and 3+ for more than mod-
erate immunostaining
[18]
. Trastuzumab was associated with an increase in the objective
response rate from 32% to 50%, longer median survival, and a 20% reduction in the risk of
death. Retrospective analysis of HER2 expression by IHC and copy number differences by
FISH revealed that the antibody was most active in patients with 3+ HER2 staining intensity
or HER2 gene amplification. No patient with 2+ HER2 IHC staining had a response unless
gene amplification was detected by FISH.
Due to the increased response rate in HER2+ patients, multiple clinical tests have been
approved for use in tumor biopsies to measure HER2 protein levels or gene amplification
or other changes in HER2 activation in order to select patients more likely to respond to this
therapy
[15-18,24]
. All HER2 tests have been validated by retrospective analyses and were
not used to qualify patients for enrollment in studies leading to the initial approval of tras-
tuzumab by the FDA. HER2 testing has continued to evolve, with many clinical laboratories
using both FISH and IHC to evaluate HER2
[18]
. IHC remains the most frequent initial test
for HER2 status and is performed on approximately 80% of newly diagnosed breast cancers
in the US. Advantages of IHC testing include its broad availability, relatively low cost, and
easy preservation of stained slides, with disadvantages including lack of a positive internal
control and difficulties interpreting the semi-quantitative subjective scoring system of 1+, 2+,
3+
[16]
. On the other hand, FISH has a more objective scoring system and an internal control
due to known levels of the HER2 gene in cells that do not have gene amplification. FISH
can be more expensive than IHC and does not allow for long term preservation and stor-
age of slides, but is considered to be more reproducible
[25-27]
. Currently, testing for HER2
status often starts with screening by IHC, where results of 0 and 1+ are considered nega-
tive, 2+ is considered equivocal and referred for FISH testing, and 3+ is considered positive
[16]
. Although this is the most typical testing algorithm in clinical practice, numerous tests
using other methodologies have been approved to measure HER2 status in BC (
Table 2.1
).
Unfortunately, clear understanding of how to interpret the results from each of these tests
and utilize them to impact treatment decisions is still lacking
[24]
. The ability to correctly
identify HER2+ patients is important because patients misclassified as HER2− will be denied
potential benefit from anti-HER2 therapies and those misclassified as HER2+ may endure
potentially toxic and expensive therapy with little chance of clinical benefit.
Although the issues with HER2 testing results are important, the more critical issue may
be that the NPV of the HER2 test is high, but the PPV is only around 25-40%
[18,28,29]
,
indicating that about 60-70% of HER2 positive patients do not respond to HER2 targeted
therapy. With a low PPV of measuring HER2 alone (by any test) and resistance developing
Search WWH ::
Custom Search