To understand anti-HER2 targeted therapy for breast cancer, it’s important to first understand what HER2 is and what a positive HER2 means.
HER2 is a growth factor receptor on cells, the full name is called human epidermal growth factor receptor 2. It receives stimulatory messages from the body to accelerate tumor cell growth and division. HER2 positive means that breast cancer is more malignant and patients have a relatively poor prognosis. HER2 positive breast cancer accounts for about 20% of all breast cancers.
In order to treat HER2 positive breast cancer, people have found ways to develop drugs that target HER2 in a variety of ways. The film Proof of Survival documented the development of the first anti HER2 targeted drug, trastuzumab, which was later shown to significantly reduce the risk of death and provide a survival benefit to patients with HER2 positive breast cancer.
But HER2 positive breast cancer is a biologically heterogeneous disease. It is also HER2 positive breast cancer, but patients have different pathogenesis and therefore respond differently to drugs, presenting different characteristics and clinical outcomes.
In recent years, multiple mechanisms of anti HER2 targeted drugs have emerged, and most clinical studies of new drugs in combination with trastuzumab have attempted to eliminate HER2 positive breast cancer cells by “serial killing” them.
Pertuzumab is the successor to trastuzumab as an anti-HER2-targeted agent, and the National Comprehensive Cancer Network (NCCN) breast cancer guidelines state that the so-called “dual-targeted” treatment of pertuzumab in combination with trastuzumab is more effective than trastuzumab alone.
Why does patuximab work against cancer?
Why does trastuzumab work?
Pattuzumab is a monoclonal antibody that binds to HER2 at a different site than trastuzumab. Patuximab inhibits HER2 from heterodimerizing with other members of the HER family and is theoretically more resistant to HER2.
For HER2 positive advanced breast cancer, patuximab improves patient survival
Can the powerful combination of pertuzumab and trastuzumab further improve survival in patients with HER2-positive advanced breast cancer?
A clinical study called CLEOPATRA answered this question. This study involved more than 800 breast cancer patients, half of whom received the triple combination of pertuzumab + trastuzumab + docetaxel.
The New England Journal of Medicine, the world’s leading medical journal, reported results at a follow-up of 50 months:
- The addition of pertuzumab resulted in a significant increase in disease remission in patients, from 69% to 80% .
- Pattuzumab combined with trastuzumab and chemotherapy increased the median survival time by 15.7 months to 56.5 months and reduced the risk of death by 32%.
- Progression-free survival was prolonged by 6.3 months (to 12.4 months and 18.7 months, respectively) and the risk of progressive breast cancer progression was reduced by 32% with pertuzumab treatment.
As we can see from the data above, the “double whammy” of pertuzumab combined with trastuzumab can lead to better survival in patients with HER2-positive advanced breast cancer. on June 8, 2012, pertuzumab was approved in the United States for HER2 positive metastatic breast cancer.
Pattuzumab neoadjuvant therapy to improve pathologic complete remission of breast cancer
Neoadjuvant therapy, which is treatment administered prior to breast cancer surgery, aims to reduce tumor size and stage, thereby allowing some patients with inoperable breast cancer to have access to surgery or to breast conservation in patients who would not otherwise be candidates for breast-conserving surgery. After neoadjuvant therapy, the tumor is evaluated for changes.
Does pertuzumab combined with trastuzumab achieve better tumor control when treating HER2-positive breast cancer before surgery?
The NeoSphere study is a phase II clinical trial. In this study, 417 patients with locally advanced, inflammatory, or early HER2 positive breast cancer were divided into four groups and each received the following treatment regimens preoperatively:
- trastuzumab + docetaxel
- Pattuzumab + trastuzumab + docetaxel
- Pattuzumab + trastuzumab
- Pattuzumab + docetaxel
After breast cancer surgery, all patients underwent anthracycline-based adjuvant chemotherapy and completed 1 year of adjuvant trastuzumab. In terms of efficacy, the three-drug regimen of pertuzumab + trastuzumab, which constitutes a dual-targeted therapy with docetaxel, was the most efficient, with a 46% pathologic complete remission (pCR) rate in breast cancer patients, much higher than the other three drug combinations.
The pathologic complete remission (pCR) rate is defined as the absence of any signs of cancer in tissue specimens obtained by surgery or biopsy after treatment, with no cancer cells found under the microscope.
Why is the pCR rate so important? One study found that achieving a pCR before surgery predicted a potentially better outcome for breast cancer patients: overall, patients who achieved a pCR had a higher 5 year progression-free survival rate. However, this conclusion is exploratory and requires further validation.
There is another study called TRYPHAENA, which is also a neoadjuvant study of trastuzumab+pattuzumab. The pCR rate for patients treated preoperatively with “dual-targeted” combined with anthracycline-containing chemotherapy is about 57% to 66%.
These data suggest that better pathologic complete remission with stronger preoperative anti-HER2 therapy in breast cancer has the potential to translate into long-term survival benefit. 2013 October 1 2013, the United States approved pertuzumab for neoadjuvant treatment of HER2 positive breast cancer. treatment.
Adjuvant treatment with patuximab improves disease-free survival by a small margin
The “dual-targeted” regimen of trastuzumab + patuximab has been a breakthrough in both postoperative treatment of HER2-positive advanced breast cancer and preoperative treatment of HER2-positive breast cancer. Can the combination continue to improve the long-term survival rate of postoperative breast cancer patients?
The APHINITY study sought to answer this question. This phase III study enrolled 4805 patients with HER2 positive breast cancer, half of whom received postoperative adjuvant therapy with pertuzumab + trastuzumab + chemotherapy.
The results showed that:
- Dual-targeted patients experienced disease relapse in 7.1% of patients treated with dual-targeted therapy; compared with 8.7% of patients treated with single-targeted trastuzumab. Although the difference seems small, a scientific analysis found that patients treated with pertuzumab in combination with trastuzumab had a 19% lower risk of recurrence or death.
- At 3 years, 94.1% of patients treated with pertuzumab-based therapy did not experience breast cancer recurrence, compared with 93.2% of patients treated with trastuzumab in combination with chemotherapy.
- For lymph node-positive breast cancer, adding treatment with pertuzumab reduced the patient’s risk of recurrence or death by 23%. Because lymph node positivity is a high-risk factor, dual-targeted therapy has the potential to provide additional survival benefit for high-risk patients.
On December 2017 20 the United States approved patuximab for the adjuvant treatment of HER2 positive early-stage breast cancer.
How safe and well tolerated is patuximab?
The above study showed that diarrhea, anemia, and neutropenia were relatively more common in patients during patuximab treatment. Overall, the addition of patuximab did not significantly increase the risk of cardiotoxicity in patients compared with trastuzumab monotargeted therapy, but other risks such as diarrhea were slightly higher.
T-DM1 in combination with patuximab: Can “stronger” targeted drugs replace chemotherapy
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T-DM1 is an antibody-coupled drug that targets HER2 and is composed of trastuzumab and a potent cytotoxic drug (DM1) that combines both tumor targeting and chemotherapy for tumor destruction.
The KRISTINE study is a phase III study with T-DM1 at its core. In the preoperative treatment of HER2 positive early breast cancer, a subset of patients were treated with T-DM1 in combination with a patuximab regimen and another subset with a four-drug combination of docetaxel + carboplatin + trastuzumab + patuximab.
The results found that the remission rate of T-DM1 + patuximab was not as good as the four-drug regimen, but there was a significant improvement in safety and patient quality of life. This study is a useful attempt to replace chemotherapy with the potent, low-toxicity targeted agent T-DM1, but the results are less than optimal from the results.
Pattuzumab in China
In 2018 January 2018, a marketing application for patuximab was submitted in China, but it has not yet been approved.
Currently, there are several clinical studies of pertuzumab for breast cancer underway in China (No. CTR20160366, CTR20131049, CTR20130952, CTR20150679, CTR20131487, etc.). We look forward to landing patuximab soon to provide more treatment options for breast cancer patients.