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  Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 56  |  Issue : 2  |  Page : 119-123
 

FISH and HER2/neu equivocal immunohistochemistry in breast carcinoma


1 Department of Pathology, Kidwai Cancer Institute, Bengaluru, Karnataka, India
2 Department of Pathology, Cytogenetics Unit, Kidwai Cancer Institute, Bengaluru, Karnataka, India
3 Department of Medical Oncology, Kidwai Cancer Institute, Bengaluru, Karnataka, India

Date of Web Publication2-May-2019

Correspondence Address:
Kavitha Bidadli Lingappa
Department of Pathology, Kidwai Cancer Institute, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_333_18

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 » Abstract 


AIM: The aim of this study was to validate the role of fluorescence in situ hybridization (FISH) in investigating HER2/neu gene amplification (human epidermal growth factor receptor 2) in patients with HER2/neu equivocal breast cancer diagnosed on immunohistochemistry (IHC).
MATERIALS AND METHODS: This was a retrospective study conducted from January 2013 to October 2017. A total of 134 patients diagnosed with invasive breast carcinoma and HER2/neu equivocal status on IHC were analyzed. Also, the cases for the years 2016 and 2017 formed a subgroup that was analyzed further to study the impact of pre-analytical factors on IHC and FISH results.
RESULTS: A total of 134 women with HER2/neu IHC equivocal breast cancer were included in the study with a median age of 50 years (range 25–81). HER2/neu amplification by FISH was noted in 72 (54%) cases, whereas it was non-amplified in 52 (39%) cases. Ten cases were reported as equivocal even on FISH (ASCO/CAP 2013 guidelines). Polysomy 17 was noted in 55 cases (41%), of which 26 patients were≤50 years and 29 patients were >50 years of age. Twenty (36%) of these 55 cases showed HER2/neu amplification, whereas 26 (48%) cases were non-amplified and 9 (16%) cases were reported as equivocal on FISH. Also, more than half of the polysomy cases were hormone receptor negative.
CONCLUSION: IHC is a good screening tool for negative and positive results. Any patient targeted for trastuzumab therapy should undergo confirmation of HER2/neu equivocal status by FISH analysis. We also suggest that if a non-classical FISH pattern is seen, the test should be repeated with a non-centromeric chromosome 17 reference locus probe for better treatment planning.


Keywords: Breast carcinoma, FISH, HER2/neu, immunohistochemistry


How to cite this article:
Patil Okaly GV, Panwar D, Lingappa KB, Kumari P, Anand A, Kumar P, Chikkalingaiah MH, Kumar RV. FISH and HER2/neu equivocal immunohistochemistry in breast carcinoma. Indian J Cancer 2019;56:119-23

How to cite this URL:
Patil Okaly GV, Panwar D, Lingappa KB, Kumari P, Anand A, Kumar P, Chikkalingaiah MH, Kumar RV. FISH and HER2/neu equivocal immunohistochemistry in breast carcinoma. Indian J Cancer [serial online] 2019 [cited 2019 May 23];56:119-23. Available from: http://www.indianjcancer.com/text.asp?2019/56/2/119/257551





 » Introduction Top


Breast cancer is the second most common cancer in Indian women, usually seen in females between 40 and 50 years of age, with a mean age of 47 years.[1] HER2/neu (human epidermal growth factor receptor 2) was first reported as a poor prognostic factor for breast cancer in 1987.[2] It also has an adverse prognostic effect in cancers of the stomach, ovary, lung, and pancreas.[2],[3],[4],[5] The long arm of chromosome 17 bears this gene and encodes a 185-kDa glycoprotein which belongs to the family of type 1 growth factor receptor. As the ligand binds to HER2/neu protein, it undergoes dimerization followed by transphosphorylation of the intracellular domains. These phosphorylated tyrosine residues lead to the activation of various second messengers and transmembrane signaling pathways that cumulate in various biological effects.[6] HER2/neu gene overexpression has been observed in up to 25% of primary breast carcinomas. These patients have poor prognosis due to an aggressive tumor phenotype, increased risk of metastasis, and poor survival.[7] The development of trastuzumab, a HER2/neu targeted humanized monoclonal antibody, was a boon to patients and their oncologists.[8] In 1998, the United States, Food and Drug Administration (US FDA) approved trastuzumab for use in metastatic breast cancer, and it was approved as an adjuvant therapy for patients with HER2/neu positive and lymph node positive breast cancer in 2006.[9],[10],[11] In addition, HER2/neu status is also an important predictive marker for better and worse response respectively to other anti-cancer agents such as anthracyclines[12] and cyclophosphamides.[13] Accurate identification of the expression pattern of HER2/neu in patients withinvasive breast carcinoma is, therefore, an important pre-requisite for appropriate management.

HER2/neu assessment can be carried out by various methods like immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) (protein level), quantitative real-time polymerase chain reaction and microarray (RNA level), and fluorescence in situ hybridization (FISH)/chromogenic in situ hybridization (DNA level). IHC and FISH are the most commonly used FDA-approved tests.[14] IHC has some advantages over FISH in that it is quick, easy, and economical, whereas FISH is more expensive and takes a longer period of time. However, due to the quantitative nature of FISH, it is more reliable than IHC which is a semi-quantitative technique with the disadvantage of discrepancies in results due to variations in laboratory parameters.[15],[16] There is good concordance reported between these two methods for IHC scores of 3+ and 1+.[17],[18] IHC 2+ is an equivocal score with variable concordance with FISH results.[19] This study is an attempt to validate the role of FISH in investigating HER2/neu gene amplification in patients with HER2/neu equivocal breast cancer diagnosed on IHC.


 » Materials and Methods Top


This is a retrospective study from the archives of the Department of Pathology, Kidwai Cancer Institute, from January 2013 to October 2017. A total of 134 patients diagnosed with invasive breast carcinoma and HER2/neu equivocal status on IHC were analyzed. The details of the antibodies used on the Ventana BenchMark XT are given in [Table 1].
Table 1: Antibody details (automated)

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The PathVysion HER2/neu DNA probe kit II (Abbott) was used, which is designed to detect amplification of the HER2/neu gene via FISH in formalin-fixed paraffin-embedded human breast cancer tissue specimens. It uses a 226kb spectrum orange (SO) directly labelled fluorescent DNA probe specific for the HER2/neu gene locus 17q11.2-q12. The chromosome enumeration probe (CEP) 17 DNA probe is approximately 5.4 kb spectrum green for alpha satellite DNA sequence at the centromeric region of chromosome 17 (17p11.1-q11.1). The FFPE tissue block of breast cancer was selected and the area of interest marked on hematoxylin and eosin (H and E) slides. The matching area on the subsequent section cut from the block was taken for FISH analysis. The tissue was subjected to a series of deparaffinization, dehydration, and prehybridization treatments. After this, the probe was added and the sections were kept for overnight incubation. After the post hybridization wash, the sections were mounted and checked for signals. The whole slide was screened and every single discrete nucleus was examined for red and green signals. In all the cases, 100 nuclei were scored as positive, negative, and equivocal based on the American Society of Clinical Oncology (ASCO)/college of American pathologists (CAP) 2013 guidelines. According to these guidelines, a positive HER2/neu test is defined as positive if dual-probe HER2/CEP17 ratio is ≥2.0 with an average HER2 copy number ≥4.0 signals/cell or dual-probe HER2/CEP17 ratio ≥2.0 with an average HER2 copy number <4.0 signals/cell or dual-probe HER2/CEP17 ratio <2.0 with an average HER2 copy number ≥6.0 signals/cell. It is considered equivocal if dual-probe HER2/CEP17 ratio is <2.0 with an average HER2 copy number ≥4.0 and <6.0 signals/cell and negative when dual-probe HER2/CEP17 ratio is <2.0 with an average HER2 copy number <4.0 signals/cell. The readings were taken by two pathologists with discordant cases being reviewed and resolved in consultation.

The cases for the years 2016 and 2017 formed a subgroup that was analyzed further to study the impact of pre-analytical factors on IHC and FISH results.

Chi-square test was used to find the statistical significance of results in the two age groups (≤50 and >50 years).


 » Results Top


A total of 134 women with HER2/neu IHC equivocal breast cancer were included in the study, with a median age of 50 years and mode of 40 years (range 25–81). HER2/neu amplification by FISH was noted in 72 (54%) cases [Figure 1]a, whereas it was non amplified in 52 (39%) cases [Figure 1]b. Ten cases were reported as equivocal even on FISH [Figure 1]c. More than half of our cases were ≤50 years (70, 52%), while the rest were >50 years (64, 48%). However, there was no statistically significant difference in HER2/neu amplification patterns between the two age groups (amplified 56% vs. 52%, equivocal 8% vs. 6%, and non-amplified 36% vs. 42%). Polysomy 17 was noted in 55 cases (41%), of which 26 cases were ≤50 years and 29 cases were >50 years of age. Twenty (36%) of these 55 cases showed HER2/neu amplification, whereas 26 (48%) cases were non-amplified and 9 (16%) cases were reported as equivocal on FISH. Also, more than half of the polysomy cases were hormone receptor negative.
Figure 1: (a) Fluorescence in situ hybridization image showing positive results for HER2/neu gene amplification: red signals in clusters of 8–10 and 2 green signals per nucleus. (b) Fluorescence in situ hybridization image showing negative results for HER2/neu gene amplification: 2–3 red signals and 2 green signals per nucleus. (c) Fluorescence in situ hybridization image showing equivocal results for HER2/neu gene amplification: 2–5 red signals and 2 green signals per nucleus

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The hormone receptor status for estrogen receptor (ER) and progesterone receptor (PR) was also analyzed for all the cases. Most of our cases were hormone receptor negative. When the expression patterns of hormone receptors correlated with that of HER2/neu status [Table 2], 74% and 69% of ER negative and PR negative cases, respectively, showed HER2/neu amplification, whereas an inverse correlation was noted between ER expression and HER2/neu status. Several PR positive cases, however, showed HER2/neu amplification.
Table 2: Relation between hormone receptor expression and human epidermal growth factor receptor 2 status

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A total of 78 cases of invasive breast cancer with an age range of 30–81 years had undergone FISH assay following HER2/neu equivocal on IHC in the years 2016 and 2017. Of these cases, 29 were needle core biopsies (NCBs), 48 were excised specimens, and there was 1 cell block. All cases were evaluated for HER2/neu expression. The incidence of HER2/neu amplified, HER2/neu non-amplified, and HER2/neu equivocal in NCBs and excised specimens were 9 (31%) and 24 (50%), 12 (41%) and 23 (48%), and 8 (28%) and 1 (2%), respectively [Table 3].
Table 3: Human epidermal growth factor receptor 2 expression on fluorescence in situ hybridization in biopsies and excised specimens in 2016 and 2017

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 » Discussion Top


IHC and FISH are the most commonly used FDA-approved tests[14] and also the most viable tests for determining HER2/neu status in breast cancer for both clinical practice and research purposes.[20] IHC scores of 3+ and 1+ have shown a good concordance rate with FISH results,[17],[18] but when it comes to IHC 2+ there is more variability.[19] This study is an attempt to validate the role of FISH in investigating HER2/neu gene amplification in patients with HER2/neu equivocal breast cancer diagnosed on IHC.

In our study, more than half (54%) of the patients with IHC 2+ showed HER2/neu amplification on FISH, which is higher than that observed in some studies.[21],[22],[23] However, the studies carried out at other tertiary centers like ours show similar results.[24],[25] This has been attributed to a possible referral bias.[23] HER2/neu was non-amplified in 39% of cases, whereas equivocal FISH was observed in 7% of cases which is higher than the lower limit (<3%) recommended by the 2013 ASCO/CAP guidelines.[26] It is hypothesized that IHC equivocal results which do not show gene amplification (39%) are possibly due to variations in pre-analytical factors like tissue fixation and processing (which can affect the epitope retrieval process) and protein expression due to polysomy.[27],[28],[29],[30],[31],[32] The equivocal HER2 FISH category has been done away with in the 2018 ASCO/CAP Focused Update, with the recommendation that a definitive diagnosis will be rendered on additional workup with an additional observer, blinded to previous FISH results, doing a recount of at least 20 cells. If the count remains as before, the report is HER2/neu negative with a comment.[33]

Furthermore, HER2/neu status was compared between patients ≤50 years and >50 years, but there was no statistically significant difference between these two arbitrary groups. However, women ≤50 years showed comparatively more HER2/neu amplification. Incidence of polysomy 17 ranges from 10% to 50% and its identification by FISH assay is challenging.[27],[34] The presence of polysomy is associated with more unfavorable pathological features than with disomic tumors.[27],[28] We observed 55 cases of polysomy 17 in IHC equivocal women. Twenty-six women were ≤50 years and 29 women were >50 years of age. On FISH assay, 20 of these 55 cases showed HER2/neu amplification (36%). Similar findings have been observed in other studies,[27],[28],[29],[30] and it has been concluded that polysomy is an important cause of equivocal results.

Review of the literature shows that the term “polysomy 17” has been used when FISH shows an increase in the CEP17 signals. However, FISH analysis cannot assess the copy number of the entire chromosome because it is a targeted assay. Therefore, an increased number of CEP17 signals may represent a focal gain in the centromeric region of chromosome 17 and not a true polysomy 17. By using single nucleotide polymorphism array karyotype, one can differentiate between true polysomy 17 and focal gain of CEP17. True polysomy of chromosome 17 is rare and noted only in 1% of all analyzed cases.[35] Increase in CEP17 copy number by FISH attributed to focal gains rather than true polysomy 17 have been reported by other authors as well.[14],[36]

When the expression patterns of hormone receptors and HER2/neu status were studied, as observed in other studies,[31] our study also showed that ER and PR negative women had higher HER2/neu amplification: 74% and 69%, respectively. Interestingly, despite this inverse relation, a number of cases showed ER+ and HER2/neu amplification (43%) and PR+ and HER2/neu amplification (50%). Such dual positivity (ER/PR and HER2/neu) reduces the efficiency of tamoxifen (Selective estrogen receptor modulator (SERM)-selective ER modulator) because it acts as an estrogen agonist and enhances the growth of tumor cells expressing HER2/neu.[24] Therefore, such tumors are more aggressive.[37] We also noted that more than half of the cases with “polysomy 17” were hormone receptor negative.

Recently, Pai et al.[38] conducted a study to assess HER2/neu gene status in cases showing non classical FISH patterns with the CEP17 probe by using a non centromeric chromosome 17 reference locus (D17S122) probe and concluded that denominator-stable alternate probe can be used to analyze HER2/neu status in cases with FISH equivocal and complex patterns. This will help to stratify patients as HER2/neu positive or negative and aid their management.


 » Conclusion Top


Although IHC is a good screening tool for negative and positive results, any patient targeted for trastuzumab therapy should undergo HER2/neu IHC equivocal status confirmation by FISH analysis. As our country is a resource deprived one, it is recommended to confirm HER2/neu IHC equivocal cases by FISH analysis. If a non-classical FISH pattern is seen, then the test should be repeated with a non-centromeric chromosome 17 reference locus probe for better treatment planning.

Acknowledgment

All faculty members from the Department of Histopathology are gratefully acknowledged.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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