HER2 (human epidermal growth factor receptor 2)

Some genes and the proteins they make can influence how a breast cancer behaves and how it might respond to a specific treatment. Cancer cells from a tissue sample can be tested to see which genes are normal and abnormal. The proteins they make can also be tested.HER2 (human epidermal growth factor receptor 2) is one such gene that can play a role in the development of breast cancer. Your pathology report should include information about HER2 status, which tells you whether or not HER2 is playing a role in the cancer. The HER2 gene is also called the ERBB2 (Erb-B2 receptor tyrosine kinase 2) gene, so you may see it referred to by that name in some studies.

The HER2 gene makes HER2 proteins. HER2 proteins are receptors on breast cells. Normally, HER2 receptors help control how a healthy breast cell grows, divides, and repairs itself. But in about 25% of breast cancers, the HER2 gene doesn't work correctly and makes too many copies of itself (known as HER2gene amplification). All these extra HER2 genes tell breast cells to make too many HER2 receptors (HER2 protein overexpression). This makes breast cells grow and divide in an uncontrolled way.

Breast cancers with HER2 gene amplification or HER2 protein overexpression are called HER2-positive in the pathology report. HER2-positive breast cancers tend to grow faster and are more likely to spread and come back compared to HER2-negative breast cancers. But there are medicines specifically for HER2-positive breast cancers.

How your results appear in the report will depend on what test you have. There are four tests for HER2:

  • IHC test (ImmunoHistoChemistry): The ImmunoHistoChemistry test finds out if there is too much HER2 protein in the cancer cells. The results of the IHC test can be: 0 (negative), 1+ (also negative), 2+ (borderline), or 3+ (positive — HER2 protein overexpression).
  • FISH test (Fluorescence ISitu Hybridization): The Fluorescence In Situ Hybridization test finds out if there are too many copies of the HER2 gene in the cancer cells. The results of the FISH test can be positive (HER2 gene amplification) or negative (no HER2 gene amplification).
  • SPoT-Light HER2 CISH test (Subtraction Probe Technology Chromogenic ISitu Hybridization): The SPoT-Light test finds out if there are too many copies of the HER2 gene in the cancer cells. The results of the SPoT-Light test can be positive (HER2 gene amplification) or negative (no HER2 gene amplification).
  • Inform HER2 Dual ISH test (Inform Dual ISitu Hybridization): The Inform HER2 Dual ISH test finds out if there are too many copies of the HER2 gene in the cancer cells. The results of the Inform HER2 Dual ISH test can be positive (HER2 gene amplification) or negative (no HER2 gene amplification).

It's important to know which HER2 status test you had. Generally, only cancers that test IHC 3+, FISH positive, SPoT-Light HER2 CISH positive, or Inform HER2 Dual ISH positive respond to the medicines that target HER2-positive breast cancers. An IHC 2+ test result is called borderline. If you have an IHC 2+ result, ask to have the tissue retested with a more precise HER2 test: the FISH test, SPoT-Light HER2 CISH test, or the Inform HER2 Dual ISH test.

Research has shown that some breast cancers that are HER2-positive can become HER2-negative over time. Likewise, a HER2-negative breast cancer can become HER2-positive over time. If the breast cancer comes back in the future as advanced disease, doctors should consider ordering another biopsy and retest the tissue’s HER2 status.


See: Ghoncheh M1, Pournamdar Z, Salehiniya H.,Incidence and Mortality and Epidemiology of Breast Cancer in the World. 2016;17(S3):43-6.





2012 Screening Recommendations AAFP ACOG ACS USPSTF Other Guidance
Breast self - examination (BSE) Recommend against May be part of breast self-awareness 20+: BSE is optional; educate on benefits/ limitations Insufficient evidence USPSTF, AAFP, ACS, and ACOG encourage breast self-awareness and/or early reporting of breast changes
Clinical breast examination Insufficient evidence

40+: annual

20–39: every 1–3 years

40+: annual

20–39: every 1–3 years

Insufficient evidence Use of fingerpads of the middle three fingers, overlapping dime-sized circular motions and sequential application of light, medium, and deep levels of pressure recommended

40-49: individualize

50-74: biennial screening

75+, insufficient evidence

40+ offer annual

75+ individualize

40 through age of good health: offer annual

<50: individualize

50-74: biennial screening

75+, evidence lacking

Breast density influences ability to detect
MRI Consider in high risk Not for normal-risk screen Not for normal-risk screen Insufficient evidence for normal-risk screen MRI may afford very high sensitivity in detecting small masses, but is expensive, associated with IV contrast risks, do not detect all breast cancers that mammography can and is not widely available with guided biopsy
High-risk women Refer high-risk women by family history for genetic counseling and BRCA testing Early enhanced screen Annual mammogram + MRI for high-risk women 30+ Early enhanced screen High risk considered to be BCRA-positive ± ≥20% risk on a valid prediction model

AAFP, American Association of Family Practitioners; ACOG, American College of Obstetricians and Gynecologists; ACS, American Cancer Society; USPSTF, US Preventive Services Task Force.


Mammography remains the mainstay of screening for breast cancer.

Ultrasonography is commonly used for diagnostic follow-up of an abnormality seen on screening mammography, to clarify features of a potential lesion. Ultrasound is also used in some areas to supplement mammographic screening in women with dense breasts, although data supporting benefit for this are inadequate.

The role of magnetic resonance imaging (MRI) for breast cancer screening is emerging; currently, MRI screening in combination with mammography is only targeted to high-risk patients.

Newer tests, such as tomography, are under evaluation [1].

BRCA testing


had no history of cancer) who were identified with screening performed because of family history, these risk estimates should be generally useful for BRCA carriers identified in the course of such testing. In particular, these findings can inform decisions about surveillance and risk-reduction strategies (including chemoprevention and surgery) for these high-risk women.


Risk for Breast and Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers: Refining Our Estimates

Andrew M. Kaunitz, MD reviewing Kuchenbaecker KB et al. JAMA 2017 Jun 20.


Accurate estimation of age-specific risk for breast and ovarian cancer can facilitate counseling of BRCA mutation carriers. Investigators followed women enrolled in familial cancer registries primarily in the U.K., Holland, and France. Women were recruited into this cohort from 1997 to 2011 and had not undergone risk-reducing breast or gynecologic surgery; follow-up continued until 2013 (median, 5 years). A total of 6036 BRCA1 and 3820 BRCA2 mutation carriers were followed (median age at study entry, 38).

Cumulative risk for breast cancer by age 80 was 72% in BRCA1 carriers and 69% in BRCA2 carriers; for ovarian cancer, cumulative risk was 44% and 17%, respectively. Peak breast cancer incidence occurred at age 41–50 for BRCA1 carriers (28 per 1000 person-years) and age 51–60 (31 per 1000) for BRCA2 carriers. Incidence of ovarian cancer was 3.6 times higher among BRCA1 than BRCA2 carriers, with peak incidence occurring among women aged 61–70 regardless of mutation type. Cumulative risk of contralateral breast cancer 20 years after the first breast cancer diagnosis was 40% for BRCA1 carriers and 26% for BRCA2 carriers. For both BRCA1 and BRCA2 carriers, breast cancer risk rose with the number of first- and second-degree relatives with breast cancer. In contrast, ovarian cancer risk did not vary by family history.


- See more at: http://www.jwatch.org/na44423/2017/06/20/risk-breast-and-ovarian-cancer-brca1-and-brca2-mutation?query=etoc_jwonchem&jwd=000013567259&jspc=TS#sthash.OykVmJHt.dpuf





Women positive for the heritable BCRA mutation may benefit from prophylactic tamoxifen and prophylactic total mastectomy. Women whose family history is associated with an increased risk for BRCA mutation are referred for genetic counseling and evaluation for BRCA testing.

Indications for genetic referral for BRCA testing.1

  • A first-degree relative with breast cancer before age 40
  • Two or more relatives with breast or ovarian cancer at any age
  • Three or more relatives with breast, ovarian, or colon cancer at any age






Depends on Stage

Menopausal vs Premenopausal

Early-Stage Breast Cancer (Stages I and II)

At MDACC, every effort is made to integrate clinical information with imaging, pathologic staging, and molecular characteristics to optimize treatment efficacy and, whenever possible, perform breast-conserving surgery.

A multidisciplinary approach is of upmost importance, especially with regard to planning and combined-modality therapy.

Stage I breast cancer includes primary malignancies ≤2 cm in greatest dimension that do not involve the lymph nodes and microinvasive tumors that are ≤0.1 cm in greatest dimension. Stage II breast cancer encompasses primary tumors of 2 to 5 cm that can involve ipsilateral axillary lymph nodes and tumors >5 cm without lymph node involvement. All patients at MDACC (including those with DCIS) undergo receptor testing for hormone receptor status for ER and PR. In addition, patients are tested for HER2/neu status by IHC, and 2+ results are confirmed by FISH.

Stage I

Breast-Conserving Therapy

Breast-conserving surgery (BCS), or segmental resection, has revolutionized patient care for breast cancer over the last two decades. Women are able to preserve their breasts without a negative effect on survival. Breast-conserving therapy involves the surgical removal of tumor followed by radiation therapy to the breast. Multiple studies have shown that patients with stage I breast cancer treated with BCS have DFS and OS rates similar to patients treated with modified radical mastectomies (96).

There are only a few true absolute contraindications to BCS, including persistently positive resection margins, multicentric disease, diffuse malignant-appearing microcalcifications, a history of prior radiation to the breast or mantle region (for Hodgkin disease), and pregnancy, although it might be possible to perform BCS in the third trimester. Relative contraindications include a history of connective tissue disease suggesting that radiation would be poorly tolerated, centrally located tumors involving the nipple-areolar complex, and a large tumor in a small breast that might lead to a poor cosmetic result. Although the final decision about whether to offer BCS is left to the discretion of surgical colleagues, most patients who do not meet one of the absolute or relative contraindications are offered this surgical approach.


The risk of ipsilateral tumor recurrence ranges from 0.5% to 2.0% per year. Risk factors include age <35 years, an extensive intraductal component, major lymphocytic stromal reaction, peritumoral invasion, positive margins of resection, and presence of tumor necrosis.

Axillary Lymph Node Dissection

Sentinel lymph node biopsy is the standard of care for patients with clinically negative axilla. In accordance with the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial, patients undergoing BCS with T1 or T2 tumors with less than three positive sentinel nodes can forgo complete axillary dissection if they are treated with whole-breast irradiation. Otherwise, if a positive sentinel node is identified, complete axillary node dissection should be performed (97).

Radiation Therapy After Breast-Conserving Surgery

Patients with node-negative disease are treated to achieve a total dose of 50 Gy with an approximate dose of 2 Gy/d on a schedule of 5 days per week for a total of 5 weeks. A boost of radiation to the tumor bed is standard. Regional nodal irradiation is no longer used for negative axillary lymph nodes. Radiation is usually begun after chemotherapy is completed, but it can be given concomitantly with hormone-based therapy.

Adjuvant Therapy

Based on data detailed in the earlier section on adjuvant therapy, both pre- and postmenopausal women are offered chemotherapy. We do not routinely give chemotherapy to patients with node-negative breast tumors that are ER positive and/or PR positive and HER2/neu negative. For these patients, we are incorporating the use of the OncotypeDX test for an estimation of the risk of recurrence (see the “Other Systemic Therapy Topics” section). Patients with a low recurrence score are recommended for adjuvant endocrine therapy. Patients with a high recurrence score are counseled for chemotherapy followed by endocrine therapy. Patients with a mid-range recurrence score are offered a choice of either therapy. Our current standard chemotherapy is either dose-dense AC for four cycles followed by weekly paclitaxel for 12 weeks or FAC for 4 weeks preceded by weekly paclitaxel for 12 weeks.

Chemotherapy is usually initiated 2 to 4 weeks after surgery. Studies have shown that delaying chemotherapy for up to 8 to 10 weeks does not have a negative effect on the development of metastasis or survival.

Chemotherapy is administered if the absolute neutrophil count is ≥1,000/μL and platelets are ≥100,000/μL. A complete blood count with differential is checked prior to each chemotherapy cycle and weekly after the first cycle. Growth factor support is always given for dose-dense AC plus paclitaxel and TAC but otherwise is not routinely used. If both chemotherapy and endocrine therapy are used, we give chemotherapy first followed by endocrine therapy. If indicated, radiotherapy follows chemotherapy.

Endocrine Therapy

MD Andersen approach is to treat receptor-positive stage I disease using a hormonal treatment regimen. Based on the ATAC trial data discussed previously, tamoxifen is given to premenopausal women and AI to postmenopausal women. The ATLAS and ATTOM trials suggest extending tamoxifen to 10 years, which is now recommended. Postmenopausal patients are recommended to receive 5 years of an AI. Endocrine therapies are begun after completion of chemotherapy but can be given concomitantly with radiation therapy (Table 27-4). Given the results of the TEXT and SOFT trials, ovarian suppression therapy is now discussed with premenopausal patients, particularly the younger higher risk patients who received chemotherapy.





Clinical trials have supported 5 years of aromatase inhibitor treatment for postmenopausal women with hormone receptor–positive, nonmetastatic breast cancer, but some oncologists continue treatment beyond 5 years. This practice finally was addressed in a large randomized trial: Women who had already completed 5 years of letrozole received either letrozole or placebo for 5 additional years. Five-year disease-free survival was significantly higher with letrozole than with placebo (95% vs. 91%), but overall 5-year survival was similar in the two groups. Because aromatase inhibitors do have adverse effects, discussions on whether to proceed with an additional 5 years of treatment (total, 10 years) should be informed by this trial (NEJM JW Gen Med Aug 1 2016 and N Engl J Med 2016; 375:209).

Bone Metastases

Bisphosphonate Therapy

Bone is the most common site of metastatic disease at initial presentation and at the time of breast cancer recurrence. Bone metastases are often detected with a bone scan obtained in the staging of locally advanced cases or obtained because of clinical suspicion in the previously treated patient. Confirmation with plain radiographs, MRI, and/or CT is frequently needed because nearly 10% of lytic lesions may not be detected with a nuclear medicine scan. These other radiographic studies also help to delineate the extent of the metastatic disease. After bone metastases are confirmed, bisphosphonate therapy has been shown to diminish pain and decrease the rate of skeletal events and complications related to the bone metastases.

Bisphosphonate therapy should be administered with other palliative systemic treatments such as hormonal manipulation or chemotherapy. It is typically given intravenously every 3–4 weeks and continued indefinitely even though long-term studies are lacking. Regular dental exams, laboratory monitoring, and creatinine and renal function, as well as evaluation of calcium and vitamin D levels, are also recommended due to the risk of osteonecrosis of the jaw, renal insufficiency, and hypocalcemia associated with prolonged therapy.

Control of Nausea

Olanzapine for prevention of nausea and vomiting induced by highly emetogenic chemotherapy regimens

For patients receiving cisplatin and other highly emetogenic chemotherapy regimens, we suggest the addition of olanzapine on days 1 through 4 to standard antiemetic therapy (a combination of a 5-HT3 receptor antagonist, dexamethasone, and an NK1R antagonist) (Grade 2B).

The antipsychotic olanzapine may be a particularly useful agent for preventing delayed chemotherapy-induced nausea and vomiting, which is often poorly controlled with conventional antiemetics. The effectiveness of adding olanzapine to a standard antiemetic regimen was shown in a trial in which 380 patients receiving highly emetogenic chemotherapy (cisplatin or doxorubicin/cyclophosphamide for breast cancer) were randomly assigned to dexamethasone, an NK1R antagonist, and a 5-HT3 receptor antagonist plus either olanzapine (10 mg daily orally on days 1 through 4) or placebo [4]. The proportion of patients with no chemotherapy-induced nausea (the primary endpoint) was higher with olanzapine both in the first 24 hours after chemotherapy and in the delayed period. Rates of complete response (no emesis and no use of rescue medication) were also higher with olanzapine over a five-day period. Patients receiving olanzapine had more sedation on day 2 (severe in 5 percent), which resolved despite continued olanzapine. On the basis of this trial, we now suggest the addition of olanzapine on days 1 through 4 to standard antiemetic therapy for patients receiving highly emetogenic chemotherapy. (See "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults", section on 'Olanzapine'.)


Radiation Therapy

UMMC is the only center to offer the four leading radiation technologies designed to protect the heart. They include:

  • AlignRT with Deep Inspiration Breath Hold: The ideal time to deliver radiation to the left breast is when a patient takes a deep breath, which moves the heart posteriorly and inferiorly away from the chest wall. AlignRT helps radiation therapists know when patients are in this optimal position; it also allows the therapist to stop the radiation beam when the patient breathes. This technology brings down the amount of radiation reaching the heart to virtually nil and has been part of UMMC’s radiation treatment arsenal for about five years.
  •  Proton therapy: Compared to traditional photon radiation, proton therapy beams are more precise because they can be programmed to stop at the treatment site without penetrating deeper. Using this option in certain breast cancer patients — depending on tumor location and shape, as well as lymph node involvement — can reduce radiation exposure to the heart. The Maryland Proton Treatment Center, one of only about 20 such facilities in the country, opened in February 2016.
  • Thermal therapy: By heating tumors growing on the chest wall up to 110 degrees, this technology enhances the efficacy of radiation therapy. UMMC is the only center in the region offering thermal therapy.
  • GammaPod: The first device of its kind, this form of stereotactic radiation therapy was developed by UMMC faculty members. The machine is fully dedicated to treating early-stage breast cancer, and delivers a high dose of 36 focused radiation beams while patients are treated in a prone position, allowing the tumor to fall away from the chest wall. UMMC is currently conducting a preapproval trial on GammaPod for the Food and Drug Administration.{1}


Metastatic spread is often to lungs, liver, and bone.

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All of the following statements regarding the difference between breast cancer in pregnant versus nonpregnant women are true EXCEPT:



Question 1 of 2

A 61-year-old woman is diagnosed with stage II breast carcinoma. She receives a mastectomy, where she is found to have one positive lymph node. The tumor is positive for estrogen receptor, progestin receptor, and overexpression of HER2/Neu. She receives adjuvant chemotherapy with doxorubicin, cisplatin, and trastuzumab. Match the concerning toxicity with the appropriate agent.


Answer (Click)

The correct answer is C.

 Dose-dependent myocardial toxicity of anthracyclines with characteristic myofibrillar dropout is pathologically pathognomonic on endomyocardial biopsy. Anthracycline cardiotoxicity occurs through a root mechanism of chemical free radical damage. Fe3+-doxorubicin complexes damage DNA, nuclear and cytoplasmic membranes, and mitochondria. About 5% of patients receiving >450–550 mg/m2 of doxorubicin will develop congestive heart failure (CHF). Cardiotoxicity in relation to the dose of anthracycline is clearly not a step function, but rather a continuous function, and occasional patients are seen with CHF at substantially lower doses. Advanced age, other concomitant cardiac disease, hypertension, diabetes, and thoracic radiation therapy are all important cofactors in promoting anthracycline-associated CHF. The risk of cardiac failure appears to be substantially lower when doxorubicin is administered by continuous infusion. Anthracycline-related CHF is difficult to reverse and has a mortality rate as high as 50%, making prevention crucial. Monitoring patients for cardiac toxicity typically involves periodic gated nuclear cardiac blood pool ejection fraction testing (multigated acquisition scan [MUGA]) or cardiac ultrasonography. More recently, cardiac MRI has been used, but MRI is not standard or widespread. After anthracyclines, trastuzumab is the next most frequent cardiotoxic drug currently in use. Trastuzumab is frequently used as adjuvant breast cancer therapy, sometimes in conjunction with anthracyclines, which is believed to result in additive or possibly synergistic toxicity. In contrast to anthracyclines, cardiotoxicity is not dose related, is usually reversible, is not associated with pathologic changes of anthracyclines on cardiac myofibrils, and has a different biochemical mechanism inhibiting intrinsic cardiac repair mechanisms. Toxicity is typically routinely monitored every three to four doses using functional cardiac testing as mentioned earlier for anthracyclines. Cisplatin is associated with sensorimotor neuropathy and hearing loss, especially at doses >400 mg/m2, requiring audiometry in patients with preexisting hearing compromise. Carboplatin is often substituted in such cases given its lesser effect on hearing.


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