Humpath.com - Human pathology

Home > A. Molecular pathology > ERBB2 overexpression

ERBB2 overexpression

17q

Friday 12 December 2003

HER-2/neu overexpression, HER-2overexpression, neu overexpression, HER2 overexpression

The HER2 gene, located on 17q, encodes a 185-kD transmembrane tyrosine kinase receptor. Amplification of this gene with overexpression of the gene product occurs in about 30% of cases of breast cancer and is considered to be a poor prognostic indicator for this tumor.

HER2 is an important predictive marker for response to trastuzumab and lapatinib in breast cancer. It is also a powerful prognostic marker in node-positive patients.

Although the assessment of HER2 expression is most important for predicting response to anti-HER2 therapy, detection of low-level HER2 expression might also be useful in helping to select a more aggressive treatment regimen for patients ineligible for anti-HER2 therapy. (19252432)

Pathology

- ERBB2 overexpression in breast cancer (mammary carcinomas)

  • HER-2/neu gene amplification (HER2 amplification) in

- ERBB2 overexpression in gastric cancer (gastric carcinomas)

  • HER2 overexpression correlated with nodal stage, and a lymph node ratio greater than 0.5 was more common in HER2-amplified tumors than HER2-nonamplified tumors (69.2% vs. 43.3%, respectively; P=0.086). These findings suggest that further investigations of adjuvant therapy with HER2-targeted therapy for advanced GC are warranted. (21532492)

Pathology

- In advanced gastric cancer, HER2 overexpression correlated with nodal stage, and a lymph node ratio greater than 0.5 was more common in HER2-amplified tumors than HER2-nonamplified tumors (69.2% vs. 43.3%, respectively; P=0.086). (21532492)

  • These findings suggest that further investigations of adjuvant therapy with HER2-targeted therapy for advanced GC are warranted.

HER2 immunochemistry

- HER2 IHC 3+ / +++: uniform, intense membrane staining of > 30% of invasive tumor cells
- HER2 IHC 2+ / ++
- HER2 IHC 1+ / +
- HER2 IHC 0

ASCO/CAP HER2 Guidelines and recommendations

The 2007 American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP) joint guidelines defined criteria for HER2 positivity of tumors that modified those of the US Food and Drug Administration (FDA), causing some confusion and uncertainty among clinicians.

- ASCO/CAP HER2-positivity criteria Guidelines and recommendations
- ASCO-CAP Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer. Published in Journal of Clinical Oncology, Vol 25, No 1 (January 1), 2007: pp. 118-145.

The panel recommends that HER2 status should be determined for all invasive breast cancer.

A testing algorithm that relies on accurate, reproducible assay performance, including newly available types of brightfield ISH, is proposed. Elements to reliably reduce assay variation (for example, specimen handling, assay exclusion, and reporting criteria) are specified.

An algorithm defining positive, equivocal, and negative values for both HER2 protein expression and gene amplification is recommended:
- a positive HER2 result is IHC staining of 3+ (uniform, intense membrane staining of > 30% of invasive tumor cells), a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus or a FISH ratio (HER2 gene signals to chromosome 17 signals) of more than 2.2;
- a negative result is an IHC staining of 0 or 1+, a FISH result of less than 4.0 HER2gene copies per nucleus, or FISH ratio of less than 1.8.
- Equivocal results require additional action for final determination.

It is recommended that to perform HER2 testing, laboratories show 95% concordance with another validated test for positive and negative assay values.

The panel strongly recommends validation of laboratory assay or modifications, use of standardized operating procedures, and compliance with new testing criteria to be monitored with the use of stringent laboratory accreditation standards, proficiency testing, and competency assessment.

The panel recommends that HER2 testing be done in a CAP-accredited laboratory or in a laboratory that meets the accreditation and proficiency testing requirements set out by this document.

- Positive for HER2 is defined as:

  • either IHC HER2 3+ (defined as uniform intense membrane staining of > 30% of invasive tumor cells)
  • or FISH amplified (ratio of HER2 to CEP17 of >2.2 or average
    HER2 gene copy number >six signals/nucleus for those test systems without an inter
    nal control probe).

- Equivocal for HER2 is defined as:

  • either IHC 2+
  • or FISH ratio of 1.8–2.2 or average HER2 gene copy number four to six signals/nucleus for test systems without an internal control probe.

- Negative for HER2 is defined as:

  • either IHC 0-1+
  • or FISH ratio of @<@1.8 or average HER2 gene copy number of @<@four signals/nucleus for test systems without an internal control probe.

Open references

- Predictability of adjuvant trastuzumab benefit in N9831 patients using the ASCO/CAP HER2-positivity criteria. Perez EA, Dueck AC, McCullough AE, Reinholz MM, Tenner KS, Davidson NE, Gralow J, Harris LN, Kutteh LA, Hillman DW, Jenkins RB, Chen B. J Natl Cancer Inst. 2012 Jan 18;104(2):159-62. doi : 10.1093/jnci/djr490 PMID: 22138096 [Free]

- Confirmation of a low HER2 positivity rate of breast carcinomas - limitations of immunohistochemistry and in situ hybridization. Vogel UF. Diagn Pathol. 2010 Jul 29;5:50. doi : 10.1186/1746-1596-5-50 PMID: 20670419 [Free]

- Schmidt C. How do you tell whether a breast cancer is HER2 positive? Ongoing studies keep debate in high gear. J Natl Cancer Inst. 2011;103(2):87-89. (FREE Full Text)

References

- Clinicopathologic characteristics of patients with stage III/IV (M(0)) advanced gastric cancer, according to HER2 status assessed by immunohistochemistry and fluorescence in situ hybridization. Im SA, Kim JW, Kim JS, Kim MA, Jordan B, Pickl M, Han SW, Oh DY, Lee HJ, Kim TY, Kim WH, Yang HK, Bang YJ. Diagn Mol Pathol. 2011 Jun;20(2):94-100. PMID: 21532492

- HER-2 amplification is highly homogenous in gastric cancer. Bilous M, Osamura RY, Rüschoff J, van de Vijver M, Hanna W, Penault-Llorca F, Roche P. Hum Pathol. 2009 Nov 13. PMID: 19914678

- Even low-level HER2 expression may be associated with worse outcome in node-positive breast cancer. Gilcrease MZ, Woodward WA, Nicolas MM, Corley LJ, Fuller GN, Esteva FJ, Tucker SL, Buchholz TA. Am J Surg Pathol. 2009 May;33(5):759-67. PMID: 19252432

- Molecular and immunohistochemical analysis of ERBB2 expression in correlation with proliferation rate in synovial sarcoma. Krsková L, Kalinová M, Brizová H, Mrhalová M, Sumerauer D, Kodet R. Diagn Mol Pathol. 2007 Dec;16(4):211-7. PMID: 18043284