Chemotherapy vs endocrine therapy: Who should be combined with three-positive breast cancer anti-HER2 treatment?

In the just concluded 2020 breast cancer Forum (network meeting) of the oncology branch of the Chinese Medical Association, in addition to reviewing the progress of diagnosis and treatment of breast cancer in recent years and discussing hot issues, in order to make the participants think about the diagnosis and treatment of breast cancer from multiple perspectives, the conference also added a debate segment. This paper focuses on the debate of triple positive breast cancer Summarize.triple positive breast cancer refers to the breast cancer with positive hormone receptor (ER, PR) and HER2 in immunohistochemistry. The treatment of such patients mainly includes chemotherapy, targeted and endocrine therapy, but the standard treatment scheme is not unified. Therefore, today's debate is: should anti HER2 combined chemotherapy or anti HER2 combined with endocrine therapy be preferred for triple positive breast cancer Treatment.the moderators of the debate were Professor Liu Jian of Fujian Cancer Hospital, Professor Wang Xiaojia of Cancer Hospital Affiliated to University of Chinese Academy of Sciences, Professor Ling Rui of Xijing Hospital of Air Force Military Medical University and Professor Li Zhigao of Affiliated Cancer Hospital of Harbin Medical University.the pros and cons of the debate are: Professor Wang Tao, fifth medical center, General Hospital of Chinese PLA; Professor Yang Jin, First Affiliated Hospital of Xi'an Jiaotong University; Professor Fu fangmeng, Union Medical College Affiliated to Fujian Medical University; Jin Yiting, Huashan Hospital Affiliated to Fudan University; Zhou Wenbin, Jiangsu Provincial People's Hospital; Huang Liang, Affiliated Cancer Hospital of Fudan University; and affiliated doctor of Qingdao University Professor Lu Zhidong and Professor Wang Hao of Sichuan cancer hospital participated in the discussion as supporting groups of both sides.main point of view: anti HER2 therapy combined with chemotherapy should be the first choice for triple positive breast cancer. Professor Wang Tao elaborated from three aspects of essence, evidence and data.in essence, HER2 is the driving gene of breast cancer. HER2 positive breast cancer patients have poor prognosis and short survival time. The 5-year survival rate of HER2 positive patients without anti HER2 treatment is only 13.2%, and the absolute difference between HER2 positive patients and HER2 negative patients is 11.3%.according to the BIG 1-98 study, the prognosis of patients with hormone receptor positive and HER2 positive is still poor even if they are treated with endocrine therapy for 5-10 years.hormone receptor positive and hormone receptor negative based on HER2 are just like the two brothers built in Rome, namely Romulus and Remus.they are twins with HER2 positive as the essence. Their genetic materials are basically the same, and their performance shows common performance.A retrospective study of several Italian research centers published in IJC this year specifically analyzed the metastasis characteristics of HER2 positive patients combined with hormone receptor positive / negative patients, and their visceral metastasis rates were almost the same.there is interaction between hormonal receptor positive and HER2 positive signaling pathways. Therefore, it can be found from meta-analysis that HER2 overexpression may reduce the sensitivity of endocrine therapy in advanced breast cancer, and the mechanism study also found that the up-regulation of HER2 expression is one of the drug-resistant mechanisms of endocrine therapy.to sum up, we need to use "fierce drugs", that is, anti HER2 combined with chemotherapy, for triple positive breast cancer.from the perspective of guidelines, there are the following evidence to support: NCCN guideline V1 of 2019: for HER2 positive breast cancer with hormone receptor positive, chemotherapy combined with anti HER2 treatment is recommended first, and endocrine therapy may be added after chemotherapy stops; abc4 guideline: the first-line anti HER2 treatment combined with endocrine therapy is only for highly selective patients, anti-H ER2 therapy combined with chemotherapy should be the first-line treatment for HER2 positive and hormone receptor positive patients. Anti HER2 therapy combined with endocrine therapy can be used as maintenance treatment after effective anti HER2 combined chemotherapy; CSCO guidelines: in the treatment of HER2 positive recurrent and metastatic breast cancer, anti HER2 treatment combined with chemotherapy is recommended.If HER2 positive patients are combined with hormone receptor positive, anti HER2 therapy combined with chemotherapy is preferred, and some patients who are not suitable for chemotherapy or slow progress can be considered combined with endocrine therapy.from the data point of view: trastuzumab single target treatment era, M77001 study showed that trastuzumab combined with docetaxel significantly prolonged progression free survival (PFS) and overall survival (OS).further analysis shows that for HER2 positive patients, patients with hormone receptor positive use of single target combined chemotherapy, the benefit is not less than that of patients with hormone receptor negative, even higher in absolute value.the results of M77001, h0648g, hernata, US oncology and chat study established the first-line standard treatment status of trastuzumab for HER2 positive advanced breast cancer.on the contrary, no matter trastuzumab combined with anastrozole or lapatinib combined with letrozole failed to achieve the therapeutic effect of anti HER2 combination chemotherapy in the single target combined endocrine therapy of tandem study.in the era of dual target therapy, Cleopatra study showed that patuzumab + trastuzumab prolonged OS in HER2 positive metastatic breast cancer patients compared with single target plus docetaxel.on the contrary, the results of the alternative study of dual target combined with endocrine therapy in first-line treatment were worse than that of double target combined chemotherapy.in the pertain study, trastuzumab + patuzumab combined with aromatase inhibitors (AI) achieved better PFS, but the patients were selected and given induction chemotherapy.in the stage of neoadjuvant therapy, this year's ASCO conference reported the results of the head-to-head comparison of wsg-tp Ⅱ research with dual target endocrine therapy and double target combined chemotherapy.the complete remission (PCR) rate of the two groups was significantly different, which was 56.86% in the combined chemotherapy group and 23.96% in the endocrine therapy group.confirmed the superiority of anti HER2 therapy combined with chemotherapy.in conclusion, clinicians should recognize the nature of HER2 positive breast cancer.according to the existing guidelines and data, anti HER2 combined chemotherapy is recommended as the first choice for the treatment of hormone receptor positive and HER2 positive advanced breast cancer.the opposite view: anti HER2 therapy combined with endocrine therapy should be the first choice for triple positive breast cancer. Professor Yang Jin pointed out that in molecular typing, triple positive breast cancer is a unique molecular subtype, because single cell sequencing found that the gene clustering analysis of tpmbc, whether primary or metastatic, is different from ER positive or HER2 positive.in addition, in different stages of clinical treatment, there are also corresponding clinical studies found that: in the neoadjuvant therapy stage, HER2 positive breast cancer with hormone receptor positive has lower PCR rate than that with hormone receptor negative subgroup, and the PCR rate is negatively correlated with ER expression level.at the same time, the PCR rate of patients with hormone receptor positive was significantly lower than that of patients with hormone receptor negative.therefore, for such patients, the traditional anti HER2 treatment combined with chemotherapy will benefit less than those with hormone receptor negative and HER2 overexpression.in the stage of postoperative adjuvant therapy, eight years of altto studies have shown that for HER2 positive breast cancer patients, hormone receptor positive and hormone receptor negative show different recurrence patterns.therefore, HER2 positive early breast cancer should be divided into two different characteristics based on hormone receptor status and natural course of disease, which requires different follow-up strategies and ascending and descending treatment.published in oncotarget in 2015, it showed that for triple positive breast cancer, patients with hormone receptor status greater than 50% benefited less from trastuzumab combined with chemotherapy, indicating that the biological behavior of triple positive breast cancer with high expression of hormone receptor is similar to that of hormone receptor positive breast cancer and HER2 negative breast cancer, suggesting that some triple positive breast cancer patients have The possibility of treatment. the Cleopatra study mentioned by Professor Wang Tao before is actually a comparison of double target combined chemotherapy with single target chemotherapy. according to the inclusion criteria of the study, patients enrolled in the study were allowed to receive advanced first-line endocrine therapy, and combination of endocrine therapy during targeted therapy was not allowed unless progress was made. this results in the Cleopatra study, for hormone receptor positive breast cancer patients, regardless of PFS, OS, HR values are weaker than those of hormone receptor negative patients, that is, hormone receptor positive patients benefit from Cleopatra study less than hormone receptor negative patients. therefore, in the discussion part of Cleopatra study, it was pointed out that most patients died of breast cancer, and better treatment options and strategies are still worth exploring. for triple positive breast cancer, the advantages and disadvantages of single target and double target combined endocrine therapy have not been determined, let alone the advantages and disadvantages of targeted combined chemotherapy or endocrine therapy. and in the Cleopatra study, more than 20% of patients in the Cleopatra study chose endocrine therapy at the end of the trial. according to the data of the National Cancer Center of the United States from 2010 to 2015, the median OS time of patients with anti HER2 combined with chemotherapy was 46.8 months, and the 5-year survival rate was 39.8%, while that of anti HER2 combined with endocrine therapy was 56 months, with a 5-year survival rate of 47.5%. indicates that anti HER2 therapy combined with endocrine therapy can be used as the first-line treatment option in the real world. the blocking of hormonal receptor positive / HER2 positive dual pathway has also been confirmed. in the alternative study, although the combination of lapatinib, trastuzumab and AI had a PFS of only 11 months for hormone receptor positive and HER2 positive patients with advanced breast cancer, the OS reached 46 months. therefore, the future of "de chemotherapy" is very bright. in the pertain study, the median PFS of the general population was 18.89 months, while about 42% of the patients did not receive any induction chemotherapy. The PFS of trastuzumab + patuzumab combined with AI could last for 21.72 months, which confirmed that the strong dual target non intensive chemotherapy strategy based on endocrine therapy for triple positive breast cancer was satisfactory, and the first-line anti HER2 target of triple positive breast cancer patients was targeted at HER2 Sequential endocrine chemotherapy failed to reflect the value of dual targets. in addition, in the pernetta study, the first-line chemotherapy and continuous treatment mode of triple positive breast cancer is feasible and well tolerated. therefore, endocrine therapy combined with anti HER2 therapy is recommended in the NCCN guideline V4 of 2020; moreover, due to the low toxicity of endocrine therapy, for non visceral metastasis or asymptomatic visceral metastasis, especially the clinical characteristics of patients, it is recommended that endocrine therapy is sensitive to endocrine therapy [long disease-free interval (DFI) > 12 months), recurrent site limitation, inert disease and elderly patients] This kind of joint scheme. not only that, with the deepening of the study on the molecular mechanism of breast cancer, the na-pher2 study has shown that trastuzumab combined with patuzumab has been shown