7.1.1 Application of Monoclonal Antibodies in the ...
The specific binding of a monoclonal antibody to the extracellular domain of the HER-2 receptor induces tumor cell apoptosis or blocks the cell cycle.This binding mode has high specificity and affinity，allowing the drug to directly act on tumor target cells.However，the effect on the antigen-independent cells is weak or ineffective，which not only improves the efficacy of the drug，but also reduces the adverse reactions of the drug to the circulatory system and other organs.The main drugs are trastuzumab and pertuzumab.
（1）Trastuzumab（Trastuzumab，Herceptin）
Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that acts on the HER2-Neu surface protein of breast cancer cells，interfering with the biological processes of cancer cells and ultimately causing them to die.Trastuzumab selectively acts on HER-2，has high affinity，is highly targeted，acts only on cancer cells，and has less killing on normal cells.It is a representative drug for targeted therapy of contemporary breast cancer.It plays an important role in the rescue treatment，neoadjuvant and adjuvant therapy of Her-2 overexpressing breast cancer patients.
Trastuzumab is the first targeted therapy for clinical use，and the effective rate of monotherapy for HER-2 positive metastatic breast cancer is 11%to 36%.In 1998，the US FDA first approved metastatic breast cancer for Her-2 overexpression.In 2004，the EU approved its first-line treatment for Her-2 positive metastatic breast cancer.The drug has a synergistic effect with platinum，docetaxel and vinorelbine，and has an additive effect with doxorubicin，paclitaxel and cyclophosphamide，and has an antagonistic effect with fluorouracil.Smith reported the results of the H0648g clinical trial in 2001.The median survival of trastuzumab plus paclitaxel was 6.9 months longer than paclitaxel alone.In 2005，Marty et alreported a multicenter randomized clinical trial of M77001，comparing the efficacy of docetaxel plus trastuzumab and docetaxel every 3 weeks.The results showed that the efficacy of the combination was better than that of docetaxel alone，with an effective rate of 61%and 34%，respectively，with a median survival of 31.2 months and 22.0 months，respectively.In addition，docetaxel plus platinum and trastuzumab have a good disease response rate.Trastuzumab can also be combined with vinorelbine，with an effective rate of 68%to 72%.The advantage of this regimen is that the adverse effects of hair loss are mild in the case of similar effects with docetaxel.The effective rate of combination with capecitabine was 62%.
Trastuzumab was originally approved for the treatment of HER-2 positive advanced breast cancer，and several clinical trials have confirmed the value of trastuzumab in HER-2 positive early breast cancer，so trastuzumab antiserum is also approved for adjuvant therapy of HER-2 positive early breast cancer.Two clinical trials in North America were AC（doxorubicin and cyclophosphamide）*4，sequential paclitaxel*4.The NSABP B31 clinical trial was compared with or without trastuzumab.The Intergroup N9831 clinical trial compared combined，sequential or no trastuzumab.The HERA clinical trial allowed any chemotherapy regimen after HER-2 positive breast cancer surgery，and the results of combined and without trastuzumab were compared after chemotherapy.The DCIRG 006 clinical trial was designed to validate the results of a combination of anthracycline-free trastuzumab and was divided into three groups：Group 1：AC*4，followed by docetaxel（every 3 weeks）*4；Group 2：AC*4，followed by docetaxel（every 3 weeks）*4，with trastuzumab once a week，once every 3 weeks after chemotherapy，for a total of 1 year；Group 3，Docetaxel+carboplatin（every 3 weeks）*6，trastuzumab once a week，once every 3 weeks，for a total of 1 year.There are also some small sample clinical trials of vinorelbine or docetaxel*3，with or without trastuzumab for 9 weeks，sequential FEC（fluorouracil+epirubicin+cyclophosphamide）*3.Through this series of clinical studies，trastuzumab has been recommended as a standard component of adjuvant therapy for HER-2 positive early breast cancer.
After extensive clinical studies，a short course of trastuzumab（9-week or 6-month therapy）does not achieve the same efficacy as 1-year standard therapy.Although the persphone study validates 6-month therapy may benefit，certain populations but experts believe that it is not yet possible to accurately determine the best beneficiary population，so the HER-2 positive breast cancer trastuzumab adjuvant treatment standard is still recommended for 1 year.In addition，trastuzumab treatment patients who can be treated with trastuzumab again：1.New adjuvant therapy is effective；2.Relapse after one year of adjuvant therapy；3.Stop drug after effective rescue therapy.(https://www.daowen.com)
（2）Pertuzumab
Pertuzumab is another recombinant monoclonal antibody that，unlike trastuzumab，binds primarily to the extracellular domain Ⅱ region of the HER-2 receptor，inhibits the formation of dimers，and inhibits receptor-mediated signal transduction pathway.Trastuzumab binds to the extracellularⅣ region of the Her-2 receptor，and the formation of the dimer does not involve the Ⅳ region，so the trastuzumab monoclonal antibody is only effective against Her-2 overexpressing breast cancer patients，while Tobacco monoclonal antibodies are equally effective in patients with low expression of Her-2.Pertuzumab as a HER2/neu receptor antagonist，combined with trastuzumab and docetaxel，can be used for locallyadvanced，inflammatory or high-risk HER2 positive early breast cancer with recurrence（Early breast cancer，eBC）neoadjuvant therapy for adult patients（preoperative treatment）.A phase Ⅲ clinical trial of CLEOPATRA with randomized trials of pertuzumab plus trastuzumab showed trastuzumab plus docetaxel plus patoxuzem in patients with metastatic HER2 breast cancer Compared with the untreated group，the PFS was significantly improved by 18.5 months and 12.4 months（HR=0.62，P＜0.0001），and the addition of patozumab also reduced the risk of death by 36%（HR=0.64，P=0.0053），and the addition of trastuzumab did not increase toxicity on the basis of the standard treatment regimen，docetaxel plus trastuzumab.Therefore，in June，2012，the US FDA approved pertuzumab for the combination of docetaxel and trastuzumab as first-line treatments for HER-2 positive advanced breast cancer.
The NeoSphere study published in Lancet Oncology in 2012 confirmed that“trastuzumab+pertuzumab”dual-target combined with docetaxel was applied to neoadjuvant therapy for HER2-positive breast cancer in 4 cycles，and the pCR rate was obtained.The trastuzumab was significantly increased compared with the single-target group（45.8%vs 29%，P=0.0141），tpCR（39.3%vs 21.5%）.Accelerated approval（FDA）was therefore obtained as a neoadjuvant therapy for early HER2-positive breast cancer with locally advanced，inflammatory，tumor＞2 cm or N+.In addition，a 5-year follow-up of the NEOSPHERE study showed that the trapa target had a survival benefit compared to the trastuzumab single target（PFS：86%vs 81%）.
The aphinity study of pertuzumab in combination with trastuzumab for postoperative adjuvant therapy of HER-2 positive breast cancer reported the final results at the 2017 ASCO meeting.After 3 years of follow-up，the pertuzumab Conjugate's invasive disease survival（IDFS）was 94.1%in the tocilizumab and chemotherapy groups，and 93.2%（HR=0.82，95%ci：0.67 to 1.00）in the trastuzumab plus chemotherapy and placebo groups.This benefit was more pronounced in the high-risk subgroup.After 4 years of follow-up，the idfs of the patients with positive lymph nodes in the pertuzumab group were 89.9%，and the IDFS of the lymph node-positive patients in the standard treatment group was 86.7%（HR=0.77，95%Ci：0.62～0.96，p=0.019）.For hormone receptor-negative patients，the IDFS of the pertuzumab group and the standard treatment group were 91.0%and 88.7%，respectively（HR=0.76，95%ci：0.56～1.04，p=0.085）.
The recommended method of administration of pertuzumab is a 840 mg loading dose followed by 420 mg once every 3 weeks.Common adverse reactions（＞30%）with pertuzumab in combination with trastuzumab and docetaxel are diarrhea，alopecia，neutropenia，nausea，fatigue，rash and peripheral neuropathy.
The 41st San Antonio Breast Symposium（SABCS）presented the preliminary analysis of PEONY，the first phase Ⅲ study of neoadjuvant dual-target based on the Asian population.329 patients with early or locally advanced HER-2+breast cancer were enrolled in a 2∶1 ratio before surgery for 4 cycles of pertuzumab+trastuzumab+docetaxel and Pla（Placebo）+trastuzumab+docetaxel regimen.Three cycles of FEC protocol were given and 13 cycles of tricpa double target or placebo+trastuzumab regimen were administered to complete a total of 1 year of anti-HER2 treatment.The endpoint was the overall pathologic complete response rate tpCR（ypTO/is，ypNO）assessed by the patient's postoperative IRC（Independent Evaluation Committee）.The results showed that tpCR was significantly increased compared with the control group，which was nearly doubled（39.3%vs 21.8%，P=0.0014），which was highly consistent with the NEOSPHERE study.In terms of safety，it is consistent with the previously known safety data of pertuzumab，and the heart is safe.Compared with the NEOSPHERE study，PEONY is a phase Ⅲ study to validate the efficacy of tricpa dual targets in neoadjuvant therapy.At the same time，the primary end point of the PEONY study was the tpCR assessed by IRC.According to the CTNeoBC（New Assisted Breast Cancer Collaborative Study）study，tpCR can better predict long-term prognosis.