Breast cancer is considered HER2 positive if greater than 10% of cells exhibit intense staining on immunohistochemistry.
HER2 overexpression is associated with more aggressive disease, higher recurrence rate, shorten survival, as well as higher tumor grade, lymph node status, and mitotic count.
HER2 positive breast cancers grow faster and are more invasive than other types of breast cancers, they however are generally responsive to anti-HER2 therapy, improving prognosis.
Guidelines for HER2+positivity: immunohistochemistry score of 3+, dual-probe in situ hybridization with HER2/CEP 17 ratio of at least two and HER2 copy number of at least four per cell, or a HER2 copy number of at least six per cell and a immunohistochemistry score of 2+ if the HER2/CEP17 ratio is less than two.
HER2 is critical for cell survival and is important in biological processes mediated by the MAPK and PI3K pathways, such as cell growth, survival, and differentiation.
HER2 amplification and overexpression enhances and prolongs signals that trigger malignant transformation, which are associated with poor clinical outcomes in breast, ovarian, gastric, and prostate cancers.
Usually, HER2 functions as a co-receptor with other members of the HER family such as HER3 or epidermal growth factor teceptor, and activates down stream signaling pathways, including the PI3K-AKT pathway.
In HER2 positive breast cancer amplification of HER2 produces massive overexpression of HER2 resulting in uncontrolled HER2 signaling which drives breast cancer growth.
HER2 overexpression is present in approximately 20-30% of breast cancer cases.
Oncogene present in approximately 20-30% of primary invasive breast cancers.
Approximately 10% of patients with HER 2 positive breast cancer present with de novo metastatic disease.
A combined analysis of 2 trials totaling more than 3000 patients found a generally low risk of recurrence in years 5 to 10 after HER2-positive breast cancer diagnosis.
Approximately a quarter of patients with early stage HER2 positive breast cancer experience a recurrence.
Hormone receptor (HR)-positive disease HER2 – positive was associated with improved recurrence-free survival (RFS).
Unlike HR-positive HER2-negative breast cancer, the risk of late relapses in patients with HR-positive, HER2-positive disease remains unknown.
Hormone receptor negative HER2 positive (HER2 enriched tumors) is found in approximately 5% of all patients with breast cancer and is characterized by over expression of HER2 protein and lack of estrogen progesterone receptors.
The median time to recurrence or death was 2.5 years; for patients without an event, the median follow-up time was 8.0 years.
Patients who had HR-positive disease significantly better recurrence-free survival at 10 years, at 73.84% compared with 69.22% in HR-negative patients.
Chemotherapy in HER2 directed therapy is indicated for patients with node positive disease and tumors greater than 1 cm.
Preferred therapies for preoperative and adjuvant treatment are presently anthracycline sparing.
Study show with continuous follow up with this disease will recur in approximately 25-30% of patients, despite treatment with trastuzumab.
For treated with trastuzumab, the cumulative hazard for RFS among HR-positive patients during the first five years was 10.96%, compared with 17.48% for HR-negative patients, for a hazard ratio of 0.60.
The difference based on HR status disappeared, however, in years 5 to 10, with an HR of 1.32.
The overall risk of recurrence is low in years 5 to 10.
Among patients with no lymph node involvement, the risk of recurrence in those years was 3.23%; among those with involvement of 1 to 3 lymph nodes, the risk of recurrence was 6.39%.
There is persistent benefit of adjuvant trastuzumab in the long term.
HER2 positive breast cancer cells have 100 times the usual number of HER2 receptors than normal breast cells, and they are located on the outside of the cell.
Known as epidermal growth factor 2 (ERBB2).).
Currently (2021) eight drugs at target HER2 are available and include: three monoclonal antibodies, two antibodies-drug conjugates, and three oral tyrosine kinase Inhibitors.
Humanized anti-HER2 monoclonal antibodies pertuzumab and trastuzumab are more active in combination than alone because of more comprehensive signaling blockade.
Trastuzumab blocks HER2 receptors outside of the cell, preventing growth signal.
More common in younger women, but can occur at any age.
Trastuzumab has a significant improvement in the outcomes of women with early stage breast cancer with trials containing in anthracycline based therapy followed by trastuzumab with or without a taxane in women with node positive or node negative high risk breast cancer.
TOP2A, Topoisomerase IIa is an enzyme important in DNA replication and is the target of anthracyclines,and may be amplified in 1/3 of patients with HER2 positive disease:probably accounting for anthracycline advocacy in HER2 positive breast cancer.
In neoadjuvant setting, the addition of trastuzumab chemotherapy doubled the probability of achieving the pathological complete response: it is the mainstay for the treatment of HER2 positive locally advanced breast cancer.
For stage I disease simple chemotherapy and trastuzumab are successful treatments.
Using a short course of adjuvant paclitaxel plus trastusumab demonstrated a three-year invasive disease free survival of 98.7% in patients with small breast cancers 3 cm or less without microscopic nodal involvement.
The addition of pertuzumab to trastuzumab and docetaxel,as compared with the addition of placebo significantly improves the median overall survival to 56.5 months in metastatic breast cancer that is HER2 positive (CLEOPATRA Study Group).
In a randomized phase 3 study of patients with stage II and III ERBB2 positive breast cancer showed similar three-year event free survival estimates of 93% in patients treated with anthracyclines and 94% in patients treated without anthracyclines: suggesting omitting anthracyclines in early HER2 positive breast cancer.
With pertuzumab based regimen as above CLEOPATRA study, the eight year 37% survival and 16% were free of disease progression with a history of metastatic breast cancer HER2 positive
Combination of trastuzumab and pertuzumab and taxane chemotherapy accepted as first line treatment of metastatic disease.
Frontline therapy: the combination of a taxane with trastusumab and pertuzumab is the gold standard based on the CLEOPATRA study.
For second line therapy of patients previously treated with a taxane and trastusumab is Ado-trastusumab emtansine (T-DM1) the first antibody drug conjugate approved for breast cancer.
Trastusumab deruxtecan may replace T-DM1 as second line treatment.
Margetuximab a HER2 targeted monoclonal antibody Is a third line choice.
Neratinib an oral, irreversible pan – HER TKI approved in combination with capecitabine is also for third line setting.
Tucatinib an oral TKI is approved.
Approval for a fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidase (Phesgo, Genentech) for subcutaneous injection to treat adult patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer that has spread to other parts of the body.
Trastuzumab emtansine is the recommended second line therapy for HER2 positive metastatic breast cancer.
Neoadjuvant combination of trastuzumab, pertuzamab, and docetaxel is equal to trastuzumab emtansine monotherapy in HER positive breast cancer.
In a study of more than 4000 patients adding trastuzumab to chemotherapy led to a 37% relative improvement in overall survival, increasing 10 year survival from 75.2% to 84%, and the 10 year disease free survival rate increased from 62% to 73.7%(NSABP B-31).
Trastuzumab when added to chemotherapy doubled the proportion of patients achieving a pathological complete response when compared with chemotherapy alone in HER2 positive early stage operable breast cancer patients as neoadjuvant therapy.
PHARE trial found that 6 months on trastuzumab added to chemotherapy is as beneficial as 12 months of therapy.
Trastuzumab is most effective when begun concurrently with chemotherapy rather than sequentially.
Only setting that platinum use in early breast cancer is accepted as the standard of care is in HER2+ breast cancer.
HER2 targeting with a mab trastuzumab is superior to that using a TKI
ERBB2 amplified or overexpressed breast cancer benefits from ERBB2 targeted therapy including anti-ERBB2 antibodies such as trastuzumab and pertuzumab and small molecule tyrosine kinase inhibitors such as lapatinib and neratinib.
When combined with an aromatase inhibitor dual blockade with trastuzumab and lapatinib shows superior progression free survival compared with trastuzumab alone in postmenopausal women with HER2 + HR+ metastatic breast cancer.
Lapatinib can also potentially restore tamoxifen sensitivity.
Patients with a P13KCA mutations are associated with a worse prognosis inHER2 positive breast cancer and that approximately one third of HER2 positive breast cancers harbor these kinds of mutations.
BOLERO-1 and BOLERO-3 trials failed to demonstrate clinical utility of combination mTOR inhibitor everolimus with anti-HER2treatments, respectively in first-line treatmentsand trastuzumab resistant HER2 positive metastatic breast cancer.
Pembrolizumab may be efficacious in HER2 positive breast cancer patients with PD-L1 positive tumors and resistant to trastuzumab.
The immune checkpoint inhibitor pembrolizumab overcomes trastuzumab resistance in HER2-positive advanced breast cancer provided that the tumor expresses programmed death ligand 1 (PD-L1).
HER2-positive breast cancers have been observed to contain high levels of T-cell infiltration.
Tumor-infiltrating lymphocytes (TILs) are associated with improved prognosis and higher response rates to trastuzumab and chemotherapy, suggesting that modulating anti-tumor immunity could further improve survival outcomes.
With a median follow-up of 13.6 months, the cohort of patients having tumors positive for PD-L1 achieved an overall response rate of 15.2% and a disease control rate of 24%.
The response rate was almost eight times higher in patients who had at least 5% of the stromal area densely infiltrated with TILs.
Among patients with HER2-negative breast cancer, PD-L1 is not as a strong predictive biomarker.
Patients with high TILs or immune infiltration usually have high levels of PD-L1 expression on their TILs.
About 1/3-1/2 of patients with advanced HER2 positive breast cancer develop brain metastasis.
The median time to the onset of brain metastasis is 13.3 months following a diagnosis of metastatic disease.
Brain metastasis in HER2 positive disease most often develops during the first or second line therapy, whereas extracranial disease is often stable.
HER 2 positive breast brain metastasis is treated with surgical resection for solitary tumors and radiotherapy including whole brain radio therapy or stereotactic surgery.
Patients having 5% or more TILs were dramatically more likely to have a response.TIL levels vary, with higher levels seen in metastases from lung and lymph nodes, and lower levels seen in those from liver and skin.
Adjuvant anti-HER2 therapy in combination with chemotherapy has markedly improved disease-free survival (DFS) and overall survival (OS) for patients with node-negative and node-positive HER2-positive breast cancer.
The optimal use of trastuzumab is giving it concurrently with chemotherapy, and then for 1 year as maintenance therapy.
The roles of other anti-HER2 agents, pertuzumab and neratinib are not yet fully established in the neoadjuvant setting.
DFS advantages have translated into OS advantages and have improved the prognosis of patients with HER2-positive breast cancer to the magnitude seen with ER-positive breast cancer.
One year of trastuzumab has been determined to be an optimal duration, with no benefit seen from extended trastuzumab and a suggestion that 6 months may be inferior.
Trastuzumab is best given concurrently with chemotherapy before maintenance therapy.
Emphasis should be placed on providing trastuzumab concurrent with the taxane portion of chemotherapy.
Single-agent lapatinib has been proven to be inferior to trastuzumab in several trials in neoadjuvant and adjuvant settings.
After treatment with adjuvant chemotherapy and trastuzumab, about 55% to 60% of those destined to relapse will do so within the first 5 years.
In patients with residual disease after standard neoadjuvant therapy T-DM1 based therapy resulted in a three-year invasive disease free survival of 88.3% in the KATHERINE trial.
HER2-positive/ER-negative breast cancer tends to recur more quickly than HER2-positive/ER-positive breast cancer.
The overall prognosis of trastuzumab/chemotherapy treated patients with HER2-positive tumors now is as good as that of patients with HER2-negative/ER-positive tumors.
Most patients with T2N0 or node-positive HER2-positive breast cancer are treated with preoperative therapy.
Benefits from neoadjuvant therapy are possible: 1) a small percentage of patients may be able to get breast-conserving surgery instead of mastectomy; and 2) the axillary lymph nodes (LNs) may be cleared and reduce the need for postmastectomy radiation therapy, axillary LN dissection, and the size of the radiation port.
The rate of pathologic complete response (pCR) with HER2-positive breast cancer is high, particularly with the addition of pertuzumab to TCH (docetaxel, carboplatin, trastuzumab) or AC-TH (doxorubicin, cyclophosphamide, paclitaxel or docetaxel, trastuzumab).
pCR does not correlate perfectly with long-term DFS, but it identifies patients who are likely to do well and those who are not such as those with gross residual tumor, particularly if in lymph nodes.
The above trials established the value of trastuzumab with chemotherapy as adjuvant therapy included node-negative HER2-positive breast cancer.
Data suggests that even patients who have small HER2-positive tumors do have more than an insignificant risk of recurrence.
Stage I patients have a rate of recurrence somewhere between 5% to 30%.
APT trial; this trial had looked at patients who had node-negative HER2-positive tumors that were less than three centimeters and treated them in a uniform fashion with weekly paclitaxel for 12 weeks in combination with trastuzumab, with trastuzumab being given over a year’s period of time.
And the study demonstrated that there are very few recurrences seen in this treatment, and with a three-year disease-free survival of 98.7% and a seven-year recurrence rate interval of 97.5%, suggesting that patients treated with paclitaxel and trastuzumab had very good long-term outcomes.
At a a median follow-up of 65 months, OS in the 928 patients with N0 disease was 92.9%, 97.5%, and 96.2% for the AC-T (doxorubicin, cyclophosphamide, paclitaxel), AC-TH, and TCH arms of BCIRG 006.
All but the smallest HER2-positive breast cancer should be treated with neoadjuvant chemotherapy plus anti-HER2 therapy.
A year of trastuzumab clearly improves DFS and OS.
HER2 positive hormone receptor positive disease is a more indolent type of breast cancer with later onset of recurrences and similar benefits from trastusumab.
Pertuzumab can clearly increase the pCR rate when combined with trastuzumab plus chemotherapy in the neoadjuvant setting.
Low-stage node-negative disease could be treated with less-intensive chemotherapy, as the overall risk for recurrence is lower and, therefore, the absolute benefit of treatment is smaller.
Patients with T1a or T1mic N0 HER2-positive breast cancer have an outstanding outcome in the absence of treatment or just adjuvant endocrine therapy if the tumor also is ER positive.
Trastuzumab is more effective than single-agent lapatinib and is better tolerated.
T-DM1 is more effective than trastuzumab, but it is more difficult to combine with chemotherapy due to modest overlapping toxicities, specifically peripheral sensory neuropathy, mild thrombocytopenia, and liver enzyme abnormalities.
Neratinib, an irreversible epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, may be slightly more potent than trastuzumab.
The I-SPY2 randomized, Phase II protocol tested neratinib/paclitaxel versus trastuzumab plus paclitaxel, each followed by AC preoperatively, and reported that there was a higher probability of achieving pCR among patients in the neratinib arm.
Neratinib improves progression free survival compared with lapatinib in women with metastatic HER2 positive breast cancer who have received at least two prior regimens (NALA study).
FDA Approves sNDA for Neratinib in Combination with Capecitabine for HER2+ Breast Cancer
NALA trial demonstrated that neratinib in combination with capecitabine offers a significant improvement over currently available therapies in a heavily pretreated patient population.
In the phase III clinical trial, 621 patients were randomized 1:1 to receive either 240 mg of neratinib orally once daily on days 1-21 of the study in combination with 750 mg/m2 of capecitabine given orally twice daily on days 1-14 for each 21 day cycle (n = 307) or 1,250 mg of lapatinib (Tykerb) orally once daily on days 1-21 in combination with 1,000 mg/m2 of capecitabine given orally twice daily on days 1-14 for each 21-day cycle.
Treatment with neratinib in combination with capecitabine resulted in a statistically significant improvement in progression free survival (PFS) compared to treatment with lapatinib plus capecitabine.
The PFS rate at 12 months was 29% for patients who received neratinib plus capecitabine vs 15% for patients who received lapatinib plus capecitabine and the PFS rate at 24 months was 12%, respectively.
The median overall survival (OS) was 21 months for patients who received neratinib in combination with capecitabine compared to 18.7 months for those who received lapatinib in combination plus capecitabine.
The ORR was 32.8% vs 26.7% respectively, and the median duration of response was 8.5 months vs 5.6 months, respectively.
Currently, the recommended dose of neratinib for advanced or metastatic breast cancer is 240 mg (6 tablets) given orally once daily with food on days 1-21 of a 21-day cycle plus capecitabine (750 mg/m2 given orally twice daily) on days 1-14 of a 21-day cycle until disease progression or unacceptable toxicities.
In the ExteNET trial neratinib administered after chemotherapy and trastuzumab, significantly reduced the percentage of clinically relevant breast cancer relapses.
For node-positive or large primary tumors, the TCHP regimen is per current National Comprehensive Cancer Network (NCCN) guideline.
For T1cN0 typically TCH-6 cycles is used, and for T1b, I typically the TH regimen is used.
Patients with T1mic or T1aN0 likely would not receive adjuvant trastuzumab.
In ER and HER2 positive disease, these tumors appear to be partially resistant to both endocrine and anti-HER2 therapies.
The NSABP-B52 trial compared TCHP-estrogen deprivation in the preoperative setting; the addition of concurrent endocrine therapy did not significantly increase the pCR rate.
KATHERINE trial randomized HER2 positive patients with significant residual cancer burden after neoadjuvant HER2 therapy to either trastuzumab or T-DM1 out to a year of total therapy.: T-DM1 improved invasive disease free survival by 11.3% at a median of 41 months follow up.
At 10 years of follow up in the KATHERINE trial nearly half of patients with a residual invasive breast cancer in the breast or lymph nodes after preoperative systemic therapy will have experienced clinically apparent cancer recurrence or will have died.
In the above study patients treated with T-DM1 with 50% less likely to experience recurrence of invasive breast cancer deaths than patients treated with trastuzumab.
APHINITY trial 4804 patients with early breast cancer randomly assigned postoperatively to receive chemotherapy and trastuzumab plus either perttuzumab or placebo: at a median of45.4 months follow up there was an absolute difference of only 0.9 percentage points 93.2% versus 94.1%.
APHINITY trial results at six years showed a clinical benefit of pertuzumab in patients with early HER2 positive cancer and node positive disease and the absolute benefit of 4.5% for the rate of invasive disease free survival.
Tucatinib Improves PFS, OS in HER2-Positive Metastatic Breast Cancer
Tucatinib improve survival date in patients with brain metastases.
Pembrolizumab-Trastuzumab Combo Safe, Active in PD-L1Positive, HER2-Positive Breast Cancer
Adding pembrolizumab to trastuzumab therapy is safe and has durable clinical benefit in patients with trastuzumab-resistant, advanced, HER2-positive breast cancer and PD-L1 positive tumors.
Of the 40 patients with PD-L1 positive tumors, 15% achieved an objective response. No objective responses were reported among the patients with PD-L1 negative tumors.
Pembrolizumab plus trastuzumab was safe and showed activity and durable clinical benefit in patients with PD-L1-positive, trastuzumab-resistant, advanced, HER2-positive breast cancer,
Approved tucatinib for use in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) for the treatment of patients with unresectable locally advanced or metastatic HER2-positive breast cancer, including patients with brain metastases, following at least 1 prior anti-HER2-based regimen in the metastatic setting.
Phase II HER2CLIMB trial, showed that the tucatinib triplet reduced the risk of death by 34% compared with trastuzumab and capecitabine alone in heavily pretreated patients with unresectable locally advanced or metastatic HER2-positive breast cancer.
The median overall survival (OS) was 21.9 months with the tucatinib triplet compared with 17.4 months with trastuzumab and capecitabine alone.
The 1- and 2-year OS rates were 76% versus 62% and 45% versus 27% in the tucatinib and control arms, respectively.
Because of new therapies HER2 positive metastatic breast cancer is acting more like a chronic disease,with a median survival of about five years, and about 40% of patients alive eight years later plus:trastuzumab, pertuzumab.
((Trasuzumab Deruxtecan)) s an antibody-drug conjugate consisting of a humanized , monoclonal, anti-HER2 antibody bound to cytotoxic topoisomerase I inhibitor by means of a cleanable, tetrapeptide based linker for the treatment of patients with metastatic HER2 positive breast cancer.
Trasuzumab Deruxtecan has demonstrated efficacy in patients with ERBB2 low breast cancer
Large scale retrospective analysis finds minimal prognostic differences between ERBB2-low and ERBB2-negative breast cancer: outcomes in ERBB2 low breast cancer is driven by ERBB2, directed antibody, drug conjugates, rather than intrinsic differences in biological characteristics associated with low level ERBB2 expression.
ERBB2 low tumors are heterogeneous, consisting of both hormone receptor, positive and triple negative breast cancer.
Margetuximab is a chimeric IgG monoclonal antibody against HER2 designed for the treatment of cancer.
The optimal first line choice for most patients with metastatic disease remains a taxane combined with pertuxumab and trastuzumab.