HER2 Positive Carcinoma



HER2 Positive Carcinoma







Key Facts


Clinical Issues



  • 15-20% of breast carcinomas overexpress HER2



    • All newly diagnosed invasive breast cancers should be evaluated for HER2


    • IHC, FISH, and CISH methods have received FDA approval


  • HER2+BC is associated with poorer prognosis



    • Higher incidence of lymph node metastases


    • Distant metastases are often to visceral sites and brain


  • HER2-targeted treatment is available



    • HER2+BC shows the highest responses to neoadjuvant therapy


  • HER2 status also may be predictive for response for different types of chemotherapy and endocrine therapy


  • Some HER2+BC is resistant to treatment or develop resistance to treatment



    • May be due to varying numbers of coamplified genes in different cancers or due to heterogeneity of HER2 overexpression


Microscopic Pathology



  • Majority of HER2+BC are of no special type (“ductal” carcinomas)



    • Other subtypes that can be HER2(+) are apocrine carcinoma, invasive micropapillary carcinoma, and inflammatory carcinoma


  • Usually poorly differentiated and have high proliferative rate


  • Extensive DCIS and multiple foci of invasion are more common than in other subtypes







HER2 overexpression is most frequently associated with carcinomas of high nuclear grade that typically show increased mitotic activity image and are of no special histologic type (“ductal”).






HER2(+) carcinomas demonstrate an intense “chicken wire” pattern of membrane positivity (the nucleus and cytoplasm are unstained) that is typically uniformly distributed throughout the tumor.


TERMINOLOGY


Abbreviations



  • HER2 positive breast cancer (HER2+BC)


Synonyms



  • HER2 (human epidermal growth factor receptor, HER-2/neu, c-erbB2, NEU, NGL, TKR1, CD340, ERBB2)


Definitions



  • Carcinomas characterized by overexpression of HER2: 15-20% of all breast carcinomas


ETIOLOGY/PATHOGENESIS


HER2+BC Biology



  • HER2 encodes a 185 kDa membrane tyrosine kinase growth factor receptor located on chromosome 17q12



    • Member of family of genes that includes epidermal growth factor receptor (EGFR or HER1)


  • Gene amplification results in increased mRNA and protein overexpression



    • HER2 overexpression likely plays role in carcinogenesis and tumor formation


    • Majority of HER2+BC continues to express HER2 with recurrence (lymph node and distant metastases)


  • HER2 overexpression increases receptor activation and HER receptor family signaling



    • Signaling promotes angiogenesis, proliferation, cell survival, invasion, and metastasis


  • Adjacent genes are coamplified with HER2



    • Carcinomas vary in number of genes amplified; at minimum 6 genes (and likely several dozen) are coamplified


    • Only a subset of these genes show overexpression of protein products


    • Variations in number of coamplified genes may explain some differences in response to HER2-targeted therapy


  • HER2+BC also frequently displays amplification of other DNA segments



    • 70% of these carcinomas amplify at least 1 other DNA segment


    • CEP17 (chromosome 17 centromere enumeration probe) sequences are amplified in 10-20% of these carcinomas


    • True chromosome 17 polysomy (duplication of entire chromosome) is rare: Only 1-2% of cancers


    • Relationship of CEP17 amplification to HER2 overexpression is unclear


Gene Expression Profiling



  • Molecular subtypes of breast cancer include luminal A, luminal B, HER2, and basal-like cancers



    • HER2+BC by gene expression studies are ER negative (10-20% of cancers)


    • ER(+) luminal B carcinomas (15-20% of cancers) overexpress HER2 in up to 50% of cases



      • ER positive but often at lower levels than in luminal A carcinomas


      • HER2 downregulates PR, and many of these carcinomas lack PR expression


      • Some studies using IHC to classify breast cancers have defined all luminal B carcinomas as HER2 positive


      • However, up to 50% of luminal B carcinomas by gene expression studies are HER2 negative


  • HER2 expressing carcinomas detected clinically are included in luminal B and HER2 groups



    • These patients show similar benefit from HER2-targeted therapy in clinical trials


  • Approximately 1/2 of HER2 carcinomas are ER positive and 1/2 ER negative


  • HER2 expression profile includes increased expression pattern for HER2 as well as other adjacent coamplified genes



CLINICAL ISSUES


Epidemiology



  • Incidence



    • HER2+BC reported in 15-20% of patients


  • Age



    • HER2+BC patients are younger (˜ 53 years) than the average woman with breast cancer (˜ 61 years)



      • HER2+BC is not associated with BRCA1 or BRCA2


  • Gender



    • HER2+BC is less common in males than in females


  • Ethnicity



    • No significant differences in HER2+BC rates in different ethnic populations have been reported


Laboratory Tests



  • HER2 overexpression can be documented by evaluation of DNA, mRNA, and protein assays



    • DNA analysis for gene amplification is usually evaluated by fluorescent in situ hybridization (FISH)



      • Chromogenic in situ hybridization (CISH) is alternative technique


      • 2nd probe often used to evaluate number of copies of centromere 17


      • Criteria for gene amplification utilize total number of genes or ratio of genes to number of centromere copies


      • In majority of cases, both methods of evaluation yield same interpretation


      • If the 2 methods give discordant results (usually due to increased centromere copies), it is not yet clear whether these carcinomas respond to HER2-directed therapy


    • HER2 mRNA level is evaluated and reported as part of Oncotype DX assay (Genomic Health; Redwood City, CA)



      • Should not be used to select patients for targeted therapy


    • Protein overexpression is analyzed by IHC



      • Correlation between IHC and FISH results is > 90%


      • Rare carcinomas may overexpress protein due to mechanisms other than gene amplification


      • It is easier to detect heterogeneity in HER2 expression and discordant expression patterns for DCIS and invasive carcinoma using IHC


  • IHC, FISH, and CISH methods have received FDA approval for assessing HER2 status in clinical practice


  • If HER2(+) is discordant with histologic features (e.g., carcinoma is well differentiated or subtype unlikely to show overexpression), repeat &/or additional studies should be considered


Natural History



  • HER2+BC is associated with poor prognosis



    • Higher rate of recurrence and mortality in patients with newly diagnosed breast cancer who do not receive any adjuvant systemic therapy



      • Early recurrence more commonly seen compared with HER2 negative disease


    • Small carcinomas (< 1 cm) with negative nodes have worse prognosis if HER2(+)


    • HER2+BC has worse prognosis if also ER(+)



      • May be due to higher incidence of lymph node metastases and lower response rates to therapy


  • Metastatic HER2+BC usually also overexpresses HER2



    • In rare cases, recurrent or metastatic disease lacks HER2 expression



      • Likely due to heterogeneity of expression in primary carcinoma with possible selection of subclones after treatment


      • For example, residual disease after neoadjuvant treatment with HER2-targeted therapy can lack expression in up to 1/3 of cases


  • HER2+BC more likely to spread early to major visceral sites (brain, lungs, liver, adrenals, ovaries)



    • With HER2-targeted therapy, progressive visceral disease significantly diminished


    • CNS metastases more common after treatment with HER2-targeted therapy



      • May be related to inability of trastuzumab to cross blood-brain barrier



Treatment



  • Adjuvant therapy



    • HER2 positivity may be associated with relative, but not absolute, resistance to endocrine therapy



      • Effect may be specific to selective estrogen receptor modulator therapy, such as tamoxifen


    • HER2 status may be predictive for either resistance or sensitivity to different types of chemotherapies



      • HER2 positivity is associated with response to anthracycline therapy


      • Anthracycline sensitivity may be secondary to coamplification of HER2 with topoisomerase II α (TOP2A)


      • TOP2A amplification occurs in about 1/3 of HER2+BC and is associated with ER(+)


    • HER2-targeted therapy has demonstrated remarkable efficacy in both metastatic and adjuvant settings



      • Trastuzumab (humanized monoclonal antibody) targets an extracellular epitope of HER2 receptor


      • Trastuzumab improves response, time to progression, and survival when used alone or with chemotherapy in metastatic breast cancer


      • Adjuvant trastuzumab given during &/or after chemotherapy results in significant improvement in disease-free and overall survival


      • Lapatinib (small molecule tyrosine kinase inhibitor) improves outcome in patients with advanced disease in combination with chemotherapy


    • Only patients with HER2+BC are candidates for HER2-targeted therapy



      • HER2 is a useful marker for therapeutic decision making for patients with breast cancer


      • HER2(+)/ER(-) carcinomas have best response to neoadjuvant therapy


      • HER2(+)/ER(+) carcinomas have lesser response to neoadjuvant therapy, and response is related to degree of ER expression


MICROSCOPIC PATHOLOGY


Histologic Features



  • Majority are invasive carcinomas of no special histologic type (“ductal carcinomas”)



    • Majority have high nuclear grade and DNA aneuploidy


    • Necrosis present in ˜ 40%


    • Lymphocytic infiltrate in ˜ 60%


    • More likely to harbor P53 mutations


    • High mitotic rate and proliferative index


    • Lymph-vascular invasion more common


    • More likely to be associated with extensive DCIS and multiple foci of invasion


    • Lymph node metastasis and > 4 lymph node metastases more common


  • Some subtypes of breast carcinoma have higher rates of HER2 positivity



    • Apocrine carcinoma: ˜ 50%


    • Inflammatory carcinoma: 40-50%


    • Invasive micropapillary carcinoma: 30-50%


  • Some subtypes of breast carcinoma do not overexpress HER2 or have very low rate of HER2 positivity (< 5%)



    • Tubular carcinoma


    • Mucinous carcinoma


    • Invasive papillary carcinoma


    • Triple negative carcinomas (including medullary carcinoma, basal-like carcinoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, and metaplastic carcinoma)


  • Frequency of HER2 expression in invasive lobular carcinoma is dependent on grade

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Jul 6, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on HER2 Positive Carcinoma

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