HER2


Article Author:
Sara Albagoush


Article Editor:
Faten Limaiem


Editors In Chief:
Sebastiano Cassaro
Joseph Lee
Tanya Egodage


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
12/29/2018 11:12:21 AM

Introduction

The HER2 receptor, (previously called HER2/Neu), is a transmembrane glycoprotein with tyrosine kinase activity. It belongs to the epidermal growth factor receptor family EGFR/ErbB. These receptors are essential in controlling epithelial cell growth and differentiation.[1]

The importance of these receptors is that the aberrant HER2 protein overexpression has associations with some human gynecological adenocarcinomas including breast, ovary, endometrium, cervix as well as non-gynecological cancers such as lung, gastric and bladder cancers. The protein is strongly associated with increased disease recurrence and known to be a poor prognostic factor for survival. For this reason, HER2 is a target for therapy of various types of cancer.

HER2 amplification or overexpression occurs in approximately 20-30% of human breast cancers.[2] 

Etiology and Epidemiology

HER2 amplification or overexpression occurs in approximately 20-30% of human breast cancers,[2] and some ovarian and gastric cancers, and it confers worse biological behavior and clinical aggressiveness in breast cancer.

Overexpression of HER2 is primarily attributed to HER2 gene amplification and results in constitutive activation of the HER2 downstream signaling pathway.[3] Breast cancers can possess up to 25 to 50 copies of the HER2 gene and up to a 40- to 100-fold increase in HER2 protein resulting in 2 million receptors expressed at the tumor cell surface.[4] 

HER2 amplification is a seminal event in human breast tumorigenesis, occurring in almost 50% of in situ carcinomas.[5] The fact that only 20% of invasive breast cancers are HER2 amplified suggests that many HER2-amplified in situ cancers never progress to the invasive stage.

HER2-amplified breast cancers have unique biological and clinical characteristics such as increased proliferation rates, high histologic and nuclear grade, low ER and PR levels, more aneuploidy, tendency to metastasize to CNS and viscera, relative resistance to endocrine therapy, increased sensitivity to doxorubicin.

Pathophysiology

Human epidermal growth factor receptor-2 (HER2) is a member of the epidermal growth factor family of tyrosine kinase receptors. This family includes HER1(Erb1), HER3 ( Erb3), and HER4 (Erb4) besides HER2. HER receptors are essential for cell proliferation, differentiation, and survival. 

All HER proteins share common structural features including extracellular ligand-binding domain and transmembrane domain and intracellular protein tyrosine kinase domain.[3] For HER1, HER3, HER4, they have a total of 11 extracellular ligands. HER2 makes an exception as it doesn't bind any ligand.[6]

Activation of HER2 mediated signaling pathways occurs by heterodimerization with ligand-activated EGFR or HER3 or by homodimerization when it is present in high concentrations such as in cancer. These dimerizations would lead to phosphorylation of tyrosine residues which initiates downstream signaling cascades such as PI3K/AKT signaling cascade, Ras/MEK/ERK, and JAK/STAT, that regulate cell survival, proliferation, differentiation, motility, apoptosis, survival, invasion, migration, adhesion, and angiogenesis.[3] 

Observation shows that HER3 plays an essential role in HER2- mediated oncogenic signaling.[7] HER3 lacks tyrosine kinase activity; it relies on other receptor tyrosine kinases, most notably, ERBB2 to get its tyrosine residue phosphorylated and subsequently activating the downstream signaling cascades.

HER2 containing heterodimers have the highest mitogenic potential among all HER complexes. Between all HER2 pairs, HER2/HER3 heterodimer is the most potent activator of the PI3K/AKT signaling cascade via binding of the p85 subunit of PI3K to HER3.[8] Knocking down HER3 or targeting HER3 via neutralizing antibody theoretically should reduce the growth of HER2-amplified human breast cancer.[7] Inhibition of HER2 dimerization prevents the activation of several intracellular signaling cascades including the PI3K and MAPK pathways which can cause carcinogenesis

Specimen Requirements and Procedure

Routine testing of HER2 expression is the strong recommendation on newly diagnosed patients with breast cancer as well as those with metastatic breast cancer as patients with a high level of HER2 expression would benefit from agents targeting HER2.[9] 

Cancer biopsy: tests for HER2 are usually performed on biopsy samples via either fine needle aspiration, core needle biopsy, vacuum-assisted breast biopsy of surgical excision. The sample attains a score based on the cell membrane staining pattern.

Serum: The extracellular domain of HER2 may shed from the surface of tumor cells. Using enzyme-linked immunosorbent assay ( ELIZA) to measure serum HER2 would provide a less invasive method of determining HER2 status than a biopsy.

Testing Procedures

Although there are different ways to measure the activity of HER2 oncogene activity, the best method is still controversial.

The assays used clinically are: 

  • HER2 gene amplification: via in situ hybridization (ISH), fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), polymerase chain reaction (PCR).
  • HER2 Overexpression: Western blotting, enzyme-linked immunosorbent assay (ELIZA), immunohistochemistry (IHC).[10]

All patients who tested positive for HER2 should receive HER2 directed therapy. The only test results that are predicted to benefit from anti-HER2 therapy are IHC 3+ score or FISH ratio > or equal to 2.

 ASCO/CAP recept updates suggest repeat testing if:

  • The initial test was HER2-positive in a histologic grade 1 carcinoma of infiltrating ductal or lobular carcinoma, hormone receptor positive. 
  • The presence of any of the following histologies, all of which at least 90 percent pure: mucinous, cribriform, tubular, or adenoid cystic. 

Recent 2018 ASCO/CAP guidelines compared with the 2013 guideline when using a dual-probe ISH assay, specifically the following:

  • If the HER2/CEP17 ratio is > or equal to 2.0 and an average HER2 copy number is <4.0 signals/cell.
  • If the HER2/CEP17 ratio is <2 and an average HER2 copy number is equal to or greater than 6.0 signals/cell.
  • If the HER2/CEP17 ratio is <2 and an average HER2 copy number between > or equal 4.0 and <6.0 signals/cell.

All these situations are considered HER2-positive disease as per 2013 guidelines. Currently, further workup is necessary.

Clinical Significance

Several HER2-targeted therapies have US FDA approval for breast cancer include trastuzumab, pertuzumab, ado-trastuzumab emtansine, and lapatinib. Some are still under clinical trials. The presently used agents include:

  • Trastuzumab is a monoclonal antibody. It binds to the extracellular segment of the HER2 receptors. Its mechanism of action still not fully understood. It seems to have its most significant effects in tumors with increased HER2 homodimers. Although it does not block autophosphorylation of HER2, it does inhibit HER2 downstream signaling.[11] Additionally, it may disrupt the HER2/Src interaction and may enhance antibody-mediated cytotoxicity, induces the immune-mediated response that causes internalization and downregulation of HER2.
  • Pertuzumab: is also a monoclonal antibody. It binds to the extracellular dimerization domain of HER2 and prevents it from binding to itself or other members of the EGFR family. Received in combination with trastuzumab rather than a single agent.
  • Ado-trastuzumab emtansine: Also known as T-DM1 is an antibody-drug conjugate composed with trastuzumab and emtansine the antimicrotubule agent.
  • Lapatinib: is a tyrosine kinase inhibitor against EGFR1 and HER2 inhibiting the signaling pathways down from HER2 level.[12]

Patients with HER2 positive metastatic breast cancer they usually managed with a combination of chemotherapy and HER2-directed agent. For patients with hormone receptor and HER2-positive metastatic breast cancer may receive a combination of HER2 directed therapy and endocrine therapy.

No ideal strategy exists for hormone receptor negative HER2 positive metastatic breast cancer. For those who didn't receive therapy in the past, the preference is for a combination of trastuzumab, pertuzumab, and a taxane as this was found to have improved clinical outcomes.[13] Patients who received trastuzumab and went to metastasis with a treatment-free interval of six months or longer. For patients who relapse within six months of completing adjuvant trastuzumab therapy, ado-trastuzumab emtansine is the preferred treatment option, as it improves clinical outcomes. 


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HER2 - Questions

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A 49-year-old female undergoes a breast biopsy. Immunochemical staining is positive for HER2/neu, but negative for both estrogen and progesterone receptors. Which of the following is the best treatment for this patient?



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A female has been found to have a 3 cm cancerous breast lesion. At surgery, no lymph nodes are identified. The mass is found to be positive for HER2/neu and negative for both estrogen and progesterone receptions. Which of the following is the best treatment for this patient?



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Expression of which of the following in breast cancer would indicate probable response to trastuzumab?



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Which breast cancers are referred to as "triple negative"?



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Which imaging modalities is best for detecting triple-negative breast cancer masses?



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Which of the following is true regarding triple-negative breast cancers?



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A 63-year-old female recently underwent a left lumpectomy and axillary node dissection for breast cancer. The pathology report comes back stating that she has HER2-positive status. Based on current research, besides the use of HER-targeted therapies, she will also be more likely to respond to what other treatment?



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Which of the following HER proteins does not have extracellular ligands?



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A 56-year-old woman is evaluated for right breast mass she noticed while taking a shower four weeks ago. Work up revealed stage IIA invasive ductal cancer. The cancer was estrogen receptor negative, progesterone receptor negative, and HER2 positive. Which of the following medications does not target HER2 and or HER2 signaling pathway?



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Which HER protein does not have tyrosine kinase activity?



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Which of the following statements regarding HER2 is false?



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A 61-year-old patient with ER-negative, PR-negative, HER2 positive breast cancer and a positive axillary lymph node on fine need aspiration undergoes a modified radical mastectomy with axillary lymph node dissection. Which of the following treatments is the most appropriate for this patient?



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HER2 - References

References

Klapper LN,Glathe S,Vaisman N,Hynes NE,Andrews GC,Sela M,Yarden Y, The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proceedings of the National Academy of Sciences of the United States of America. 1999 Apr 27     [PubMed]
King CR,Kraus MH,Aaronson SA, Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science (New York, N.Y.). 1985 Sep 6     [PubMed]
Yarden Y,Sliwkowski MX, Untangling the ErbB signalling network. Nature reviews. Molecular cell biology. 2001 Feb     [PubMed]
Citri A,Yarden Y, EGF-ERBB signalling: towards the systems level. Nature reviews. Molecular cell biology. 2006 Jul     [PubMed]
Baselga J,Swain SM, Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nature reviews. Cancer. 2009 Jul     [PubMed]
Christgen M,Bartels S,Luft A,Persing S,Henkel D,Lehmann U,Kreipe H, Activating human epidermal growth factor receptor 2 (HER2) gene mutation in bone metastases from breast cancer. Virchows Archiv : an international journal of pathology. 2018 Nov     [PubMed]
Sturgeon CM,Hoffman BR,Chan DW,Ch'ng SL,Hammond E,Hayes DF,Liotta LA,Petricoin EF,Schmitt M,Semmes OJ,Söletormos G,van der Merwe E,Diamandis EP, National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of tumor markers in clinical practice: quality requirements. Clinical chemistry. 2008 Aug     [PubMed]
Vu T,Claret FX, Trastuzumab: updated mechanisms of action and resistance in breast cancer. Frontiers in oncology. 2012     [PubMed]
Mamani-Cancino AD,Veloz-Martínez MG,Casasola-Busteros I,Moctezuma-Meza C,García-Cebada JM, [Frequency factor Her-2/neu overexpression in patients with breast cancer]. Ginecologia y obstetricia de Mexico. 2014 Jun     [PubMed]
Lee-Hoeflich ST,Crocker L,Yao E,Pham T,Munroe X,Hoeflich KP,Sliwkowski MX,Stern HM, A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer research. 2008 Jul 15     [PubMed]
Wolff AC,Hammond MEH,Allison KH,Harvey BE,Mangu PB,Bartlett JMS,Bilous M,Ellis IO,Fitzgibbons P,Hanna W,Jenkins RB,Press MF,Spears PA,Vance GH,Viale G,McShane LM,Dowsett M, Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Archives of pathology     [PubMed]
Di Leo A,Gomez HL,Aziz Z,Zvirbule Z,Bines J,Arbushites MC,Guerrera SF,Koehler M,Oliva C,Stein SH,Williams LS,Dering J,Finn RS,Press MF, Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008 Dec 1     [PubMed]
Baselga J,Gelmon KA,Verma S,Wardley A,Conte P,Miles D,Bianchi G,Cortes J,McNally VA,Ross GA,Fumoleau P,Gianni L, Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2010 Mar 1     [PubMed]

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