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MEDICINE

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single-probe ISH is giving the correct
answer, and it is the ratio that can in-
troduce instability by skewing the re-
sult toward a false positive or a false
negative. This ratio skewing is a result
of the segmental gains or losses
within chromosome 17 that are more
com- mon than polysomy 17 in
breast cancer.7 In addition, the
process of interchanging alternative
denominator probes does not alter
the gene copy number of the numer-
ator. According to current CAP/
ASCO guidelines, a tumor with 4 to
6 copies of the HER2 gene will be
called “HER2 equivocal” provided
the denominator generates a ratio less
than 2.0. Although reporting average
HER2 gene copy number would thus
seem to be the most straightforward
approach, substantial supporting data do not yet exist for making with borderline gene amplification (<6 copies) and low-level protein
such a change. Therefore, pathologists will need to continue to expression would be HER2-low; and tumors with no gene amplifi-
critically evaluate FISH results based on the numerator, denom- cation and no protein expression would be HER2-negative.
inator, IHC findings, and the patient’s clinical presentation. Response to Herceptin in the HER2-low category of tumors is
currently being studied in the National Surgical Adjuvant Breast and
2. How can we create an unequivocal reporting system? The cur- Bowel Project (NSABP)-B47 trial. This randomized phase III trial
rent strategy of trying to fit all breast cancers into 2 HER2 cat- is comparing chemotherapy alone with chemotherapy plus
egories for protein expression and HER2 gene copy number trastuzumab in more than 3,000 women with node-positive or high-
may not be represen- tative of the true biological spectrum of risk node-negative HER2-low invasive breast cancer.17
HER2 results. A 3-tier system including a borderline amplified The specific aim is to determine whether the addition of
group was described by Ross and colleagues in 1998 using data trastuzumab improves invasive disease–free survival in women with
from multivariate analysis of a subset (n =220) of node-negative high-risk breast cancer reported as HER2-low by IHC and FISH.
breast cancers derived from 324 cases reported by Press and col- Eligibility for the trial is determined by an IHC score of 1 to 2+
leagues in 1997.13-15 and by a HER2-to-chromosome enumeration probe ratio of <2.0,
which, together, document the presence of HER2 target receptors
A more recent retrospective study by Press et al re-interpreted on the tumor cell surface and lack of HER2 gene amplification in
enrollment and outcomes data from the Breast Cancer Research the cell nucleus.
Group clinical trials using 2013 CAP/ASCO guidelines for FISH.
Findings from more than 10,000 patients enrolled in the clinical tri- 3. Are there currently any treatment recommendations for the
als support the original FDA-approved criteria (in which there is HER2-low category of breast cancer? The NSABP-B47 trial
no equivocal category) to be strongly predictive of treatment re- began in January 2011, and its estimated primary completion
sponse.16 In this authors’ opinion, and based on these previous date is in 2017. Although there are no current treatment recom-
studies, a 3-tier system for HER2 reporting, one that recognized 3 mendations for HER2-low tumors, identifying this subtype in
categories of HER2 biology, could be considered an unequivocal high-risk patients will give clinicians insight into the HER2 bi-
reporting strategy: tumors showing high-level gene amplification ology of their patients’ tumors and provide unequivocal catego-
with high (3+) protein expression would be HER2-positive, tumors rization of the HER2 status.

20 San Antonio Medicine • March 2018