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MEDICINE

Redefining HER2-Equivocal

BREAST CANCERS:

Lessons Learned from Genomic Pathology

By Shelly Gunn, MD, PhD

Introduction lead or confuse.” Certainly, clinicians and patients who have received
It has been three decades since the human epidermal growth fac- breast cancer prognostic marker reports with HER2 equivocal re-
tor receptor 2 (HER2) was identified as an oncogenic driver of sults would agree that this term is both misleading and confusing.
human breast carcinomas.1 Now, as medical oncology enters the In my pathology consultation practice, many such cases have been
era of precision medicine, HER2 is still the most important predic- referred to me, including this recent example:
tive and prognostic biomarker in breast cancer.2 The HER2 status
of a patient’s tumor can be analyzed at the protein level by immuno- Case History
histochemistry (IHC) to visualize cell-surface receptor targets for A 69-year-old woman presents with a grade 2, <2 cm, node nega-
anti-HER2 directed therapy. Additionally, HER2 status can be eval- tive, strongly estrogen receptor–positive (ER+)/progesterone recep-
uated at the chromosome level by in situ hybridization (ISH) tech- tor–positive (PR+) tumor with HER2 initially reported as negative
niques to determine the HER2 gene copy number within the cell based on IHC score of 1+. The case was reflexed to FISH [fluores-
nucleus. Yet despite these two FDA-approved methods for HER2 cence ISH] due to “histopathologic discordance” and reported as
testing and the many biotechnological advances in clinical pathology equivocal. The HER2/D17Z1 (chromosome 17 centromere) FISH
laboratory medicine, there remains a subset of high-risk patients ratio was 1.4 (negative) “to be interpreted with caution” due to the
with breast cancer (>20%) whose HER2 status is reported (often average copy number signals per cell of HER2 4.6 and D17Z1 3.2
after multiple rounds of testing) as “equivocal.” (equivocal). The case was further reflexed for chromosome 17 “al-
Classifying a patient’s tumor as HER2 equivocal gives clinicians ternative probe” FISH where the results were reported as positive
no insight into the tumor’s HER2 biology, nor does the word pro- based on the HER2/TP53 ratio of 2.3 and HER2/SMSCR ratio of
vide any useful information about how to treat the patient. In the 2.0 [TP53 and SMSCR are chromosome 17 regions].
Merriam-Webster dictionary, the adjective “equivocal” is defined as Is it any wonder that oncologists often feel misled and confused
“subject to two or more interpretations and is usually used to mis- by pathology reports for HER2 status in breast cancer? The above

18 San Antonio Medicine • March 2018