neoadjuvant therapy refers to systemic treatment before surgery, which was initially used in patients with advanced or locally advanced breast cancer who are inoperable [1]. As treatment plans continue to enrich, it is also used to reduce the duration of breast maintenance, reduce the duration of armpit maintenance and provide patient drug sensitivity information [2,3]. Neoadjuvant therapy has been widely used in clinical practice as a standard treatment for human epidermal growth factor receptor 2 (HER-2) positive and triple-negative breast cancer (TNBC). However, due to the differences in economic levels in various regions and the uneven distribution of medical resources, some regions and hospitals still have irregular diagnosis and treatment. Therefore, the "Doctor's Daily" specially invited Professor Huang Yuanxi, an affiliated Cancer Hospital of Harbin Medical University, to conduct interviews based on the latest version of the breast cancer diagnosis and treatment guidelines and related clinical trials, from the aspects of applicable populations, selection of plans and efficacy evaluation of neoadjuvant treatment of breast cancer. In combination with clinical practice, the standardized management plan for adverse events was explored.
Neoadjuvant therapy for breast cancer applicable population
2021 American Society of Clinical Oncology (ASCO) recommends that neoadjuvant therapy is the first choice for patients with inflammatory breast cancer or patients with inresectable or locally progressive diseases. At the same time, neoadjuvant treatment is also a good choice for HER-2-positive breast cancer patients and TNBC-type breast cancer patients with high risk factors [4]. Based on the "Guidelines and Specifications for Breast Cancer Diagnosis and Treatment of Chinese Anti-Cancer Association (2021 Edition), the expert group of neoadjuvant treatment for breast cancer in China recommends: ① All patients receiving neoadjuvant treatment must clarify the pathological diagnosis and molecular typing; ② The required subjects are patients who are undergoing clinical downtime and have surgery after downtime; the preferred subjects are patients who can obtain in vivo drug sensitivity information to guide subsequent treatment [5,6]. The National Health Commission also recently announced the "Guidelines for Breast Cancer Diagnosis and Treatment (2022 Edition)". The indications for neoadjuvant chemotherapy are: ① Those who are inoperative are reduced to surgical; ② Those who are expected to reduce the period of breast conservation; ③ Neoadjuvant treatment for inoperative occult breast cancer is feasible.
Neoadjuvant therapy options for breast cancer
The B-18 and B-27 trials initiated by the American Surgery Adjuvant Breast and Intestinal Program Project Team (NSABP) show that neoadjuvant chemotherapy is comparable to adjuvant chemotherapy. Adding taxi on the basis of anthracyclines can further improve the patient's complete pathological remission rate (pCR) [7,8]. The above trial laid the foundation for neoadjuvant chemotherapy regimen based on anthracyclines and taxi. For HER-2-positive breast cancer patients, the NOAH study and the Neosphere study showed that the addition of trastuzumab and pertuzumab on the basis of neoadjuvant chemotherapy further improved the patients' pCR [9,10]. TRAIN2, KRISTINE, TRYPHENA and other experiments show that dual-target combined with taxanes and platinum drugs can obtain the same pCR rate and the incidence of adverse events is lower [11-13].
For TNBC patients, Brightness study shows that on the basis of the sequential anthracyclines of purple-shell drugs, the combination of taxa and platinum drugs significantly improves the pCR in patients and improves the prognosis [14]. GeparQuinto study showed that adding bevacizumab to standard neoadjuvant chemotherapy regimens can also improve pCR [15]. In addition, the KEYNOTE-522 trial and the Ipassion-031 trial showed that the addition of PD-1/PD-L1 on the basis of chemotherapy also had good safety and effectiveness [16,17]. For patients with luminal breast cancer, the ALTERNATE study [18] showed that the pCR rate of neoadjuvant endocrine therapy was only 1%.
Therefore, the current neoadjuvant treatment plan is still mainly neoadjuvant chemotherapy, based on molecular subtype combined with targeted therapy or endocrine therapy. Neoadjuvant treatment options for patients with HER-2-positive breast cancer
ASCO guidelines recommend that for lymph node-positive or lymph node-negative HER-2-positive breast cancer with high risk factors, use anthracycline and purple-shirt combination regimen or a dual-target regimen without anthracycline. The expert group of the Chinese Anti-Cancer Association recommended that neoadjuvant treatment of HER-2-positive breast cancer patients should adopt a dual-target-based primary option. National Health Commission guidelines recommend neoadjuvant therapy using anthracycline-containing combined taxane regimen or non-anthracycline regimen combined with trastuzumab ± pertuzumab.
combined with the above guidelines suggest that for patients with HER-2-positive breast cancer, anthracycline and taxane-based chemotherapy regimen should be given, and then trastuzumab or pertuzumab should be combined according to the patient's economic level and regional medical level.
Neoadjuvant therapy for patients with TNBC breast cancer
ASCO guidelines recommend TNBC breast cancer patients receiving anthracycline and purple shirt-based chemotherapy regimens, and carboplatin can be used as part of neoadjuvant chemotherapy regimen to increase the chance of obtaining pCR. The expert group of the Chinese Anti-Cancer Association recommends anthracycline sequential/combined taxanes as the preferred solution; in patients with higher tumor burden, especially when there is a clear BRCA1/2 mutation, a combination of platinum is recommended. The National Health Commission also recommends conventional plans containing anthracyclines and taxanes. It is also recommended that platinum can increase the likelihood of pCR as part of the scheme.
In combination with the above guidelines, for patients with TNBC breast cancer, neoadjuvant chemotherapy regimen containing anthracycline and purple shirt should be given. For platinum drugs, it is time to decide whether to use it in combination after weighing potential benefits and harms (such as with cardiac disorders). As for the application of PD1/PD-L1, since its relevant indications have not been approved in China, conventional combination of immune checkpoint inhibitors or only used in strictly designed clinical trials. Neoadjuvant treatment options for patients with HR-positive/HER-2-negative breast cancer
ASCO guidelines are recommended. For HR-positive/HER-2-negative patients, the timing of the surgery is not considered. Neoadjuvant chemotherapy can be given. For patients after menopause , neoadjuvant endocrine therapy can be given with aromatase inhibitor (AI) to increase local treatment options. For premenopausal patients, neoadjuvant endocrine therapy should not be given except for participating in clinical trials. The expert group of the Chinese Anti-Cancer Association recommends that neoadjuvant chemotherapy is the first choice for most patients at medium and high risk of recurrence. In specific patients in well-designed clinical trials, neoadjuvant endocrine therapy, preferred AI drugs (premenopausal combined with ovarian function inhibitors), fulvestrant, CDK4/6 inhibitors, or combinations with other endocrine therapy drugs are not recommended. The National Health Commission’s guidelines recommend that adjuvant chemotherapy should be recommended to advance to the neoadjuvant stage if there is a need for lowering the period or breast conservation.
combined with the above guidelines suggest that for patients with HR-positive/HER-2-negative breast cancer, the main focus should be on the selection of suitable groups. If preoperative treatment is required but is not suitable for chemotherapy, is temporarily not suitable for surgery, or does not require immediate surgery, you can consider neoadjuvant endocrine therapy alone; if there is a need for period-down or breast conservation, neoadjuvant chemotherapy ± endocrine therapy can be recommended.
Evaluation of Neoadjuvant therapy efficacy
Evaluation of Neoadjuvant therapy efficacy is divided into clinical evaluation and pathological evaluation. Clinical evaluation mainly includes physical examination , breast ultrasound, breast mammography and breast nuclear magnetism. With the continuous development of imaging technology, PET-CT and PET-MRI have also been used in the evaluation of breast cancer treatment [19-21]. One purpose of neoadjuvant therapy is to obtain drug sensitivity information in the patient's body to guide subsequent treatment. Therefore, it is especially important to have early normative assessments regardless of the tool or means used.
"Guidelines and Specifications for Breast Cancer Diagnosis and Treatment of Chinese Anti-Cancer Association (2021 Edition)" recommends that a detailed clinical examination should be conducted on the last day of the first cycle of treatment, that is, before the start of the second cycle of treatment, to have a preliminary understanding of the treatment response. Generally speaking, it is recommended to comprehensively evaluate the efficacy at the end of the second cycle of treatment, that is, before the third cycle of treatment. The evaluation results are based on the evaluation criteria for solid tumor efficacy evaluation (RECIST) version 1.1.
pathological examination is the gold standard for diagnosis, and its evaluation is more conducive to clinicians to judge the condition and formulate reasonable treatment plans. The current pathological evaluation in my country mainly includes the Miller-Payne evaluation system [22] and the residual tumor burden (RCB) evaluation system [23].
Based on clinical experience, we recommend using mammary ultrasound at least once a cycle and mammography every two cycles. Patients with financial conditions or who have multiple lesions can undergo breast nuclear magnetic evaluation before and after neoadjuvant chemotherapy.For neoadjuvant treatment, if the tumor is not retracted significantly or new tumors are new, a secondary puncture can be performed, and the treatment plan can be adjusted in time based on the results of immunohistochemistry .
Management of adverse events after neoadjuvant treatment
In the process of neoadjuvant treatment, in addition to standardized treatment plans, the accompanying systemic reactions also require strict attention. The occurrence of adverse events in neoadjuvant treatment mainly includes nausea, vomiting, bone marrow function inhibition and cardiotoxicity caused by chemotherapy. The symptoms such as nausea and vomiting caused by chemotherapy are intuitive, and in severe cases, it can lead to electrolyte disorders . For different risk regimens of vomiting, 5-HT3 receptor antagonists (such as ondansetron) may be used alone or in combination with dexamethasone and NK-1 receptor antagonists (such as aprepitane) [24]. The inhibition of bone marrow function caused by chemotherapy is manifested as a decrease in leukocytes 1-2 weeks after medication. For the deficiency of febrile neutrophils caused by different regimens, recombinant human granule cell stimulatory factor (rhG-CSF) and polyethylene glycol recombinant human granule cell stimulatory factor (PEG-rhG-CSF) can be prevented [25].
2021 "Guidelines for Standardized Management of Neutropenia Related to Tumor Chemoradiation and Chemotherapy in the Chinese Society of Clinical Oncology (CSCO) (2021)" provides an important basis for standardizing the management of neutropenia related to tumor treatment. The cardiac toxicity caused by chemotherapy mainly comes from anthracyclines. It is recommended to give prophylactic treatment to derrexon when using anthracyclines for the first time [26]. If necessary, please ask specialist for symptomatic treatment.
Summary
With the rapid development of economy and medical standards, the diagnosis and treatment level of breast cancer in my country has also made significant progress. However, the survival rate of breast cancer patients is still a certain gap with that of European and American countries. The problems that cause the above phenomena exist in many aspects, such as uneven distribution of medical resources, regional economic differences, and poor awareness of physical examinations among ordinary people. In addition, due to the characteristics of sporadic and recurrent COVID-19 epidemic, breast cancer patients, especially those receiving neoadjuvant treatment, have also been affected to varying degrees. Therefore, in this case, the standardized diagnosis and treatment of breast cancer is particularly important. Neoadjuvant therapy for breast cancer is a long-term, continuous process and a multidisciplinary treatment method. Therefore, during the diagnosis and treatment process, we must strictly follow the requirements of relevant guidelines and formulate reasonable and standardized individualized treatment plans for patients. At the same time, despite many factors that lead to delayed treatment, the management of adverse events cannot be ignored.
neoadjuvant therapy refers to systemic treatment before surgery, which was initially used in patients with advanced or locally advanced breast cancer who are inoperable [1]. As treatment plans continue to enrich, it is also used to reduce the duration of breast maintenance, reduce the duration of armpit maintenance and provide patient drug sensitivity information [2,3]. Neoadjuvant therapy has been widely used in clinical practice as a standard treatment for human epidermal growth factor receptor 2 (HER-2) positive and triple-negative breast cancer (TNBC). However, due to the differences in economic levels in various regions and the uneven distribution of medical resources, some regions and hospitals still have irregular diagnosis and treatment. Therefore, the "Doctor's Daily" specially invited Professor Huang Yuanxi, an affiliated Cancer Hospital of Harbin Medical University, to conduct interviews based on the latest version of the breast cancer diagnosis and treatment guidelines and related clinical trials, from the aspects of applicable populations, selection of plans and efficacy evaluation of neoadjuvant treatment of breast cancer. In combination with clinical practice, the standardized management plan for adverse events was explored.
Neoadjuvant therapy for breast cancer applicable population
2021 American Society of Clinical Oncology (ASCO) recommends that neoadjuvant therapy is the first choice for patients with inflammatory breast cancer or patients with inresectable or locally progressive diseases. At the same time, neoadjuvant treatment is also a good choice for HER-2-positive breast cancer patients and TNBC-type breast cancer patients with high risk factors [4]. Based on the "Guidelines and Specifications for Breast Cancer Diagnosis and Treatment of Chinese Anti-Cancer Association (2021 Edition), the expert group of neoadjuvant treatment for breast cancer in China recommends: ① All patients receiving neoadjuvant treatment must clarify the pathological diagnosis and molecular typing; ② The required subjects are patients who are undergoing clinical downtime and have surgery after downtime; the preferred subjects are patients who can obtain in vivo drug sensitivity information to guide subsequent treatment [5,6]. The National Health Commission also recently announced the "Guidelines for Breast Cancer Diagnosis and Treatment (2022 Edition)". The indications for neoadjuvant chemotherapy are: ① Those who are inoperative are reduced to surgical; ② Those who are expected to reduce the period of breast conservation; ③ Neoadjuvant treatment for inoperative occult breast cancer is feasible.
Neoadjuvant therapy options for breast cancer
The B-18 and B-27 trials initiated by the American Surgery Adjuvant Breast and Intestinal Program Project Team (NSABP) show that neoadjuvant chemotherapy is comparable to adjuvant chemotherapy. Adding taxi on the basis of anthracyclines can further improve the patient's complete pathological remission rate (pCR) [7,8]. The above trial laid the foundation for neoadjuvant chemotherapy regimen based on anthracyclines and taxi. For HER-2-positive breast cancer patients, the NOAH study and the Neosphere study showed that the addition of trastuzumab and pertuzumab on the basis of neoadjuvant chemotherapy further improved the patients' pCR [9,10]. TRAIN2, KRISTINE, TRYPHENA and other experiments show that dual-target combined with taxanes and platinum drugs can obtain the same pCR rate and the incidence of adverse events is lower [11-13].
For TNBC patients, Brightness study shows that on the basis of the sequential anthracyclines of purple-shell drugs, the combination of taxa and platinum drugs significantly improves the pCR in patients and improves the prognosis [14]. GeparQuinto study showed that adding bevacizumab to standard neoadjuvant chemotherapy regimens can also improve pCR [15]. In addition, the KEYNOTE-522 trial and the Ipassion-031 trial showed that the addition of PD-1/PD-L1 on the basis of chemotherapy also had good safety and effectiveness [16,17]. For patients with luminal breast cancer, the ALTERNATE study [18] showed that the pCR rate of neoadjuvant endocrine therapy was only 1%.
Therefore, the current neoadjuvant treatment plan is still mainly neoadjuvant chemotherapy, based on molecular subtype combined with targeted therapy or endocrine therapy. Neoadjuvant treatment options for patients with HER-2-positive breast cancer
ASCO guidelines recommend that for lymph node-positive or lymph node-negative HER-2-positive breast cancer with high risk factors, use anthracycline and purple-shirt combination regimen or a dual-target regimen without anthracycline. The expert group of the Chinese Anti-Cancer Association recommended that neoadjuvant treatment of HER-2-positive breast cancer patients should adopt a dual-target-based primary option. National Health Commission guidelines recommend neoadjuvant therapy using anthracycline-containing combined taxane regimen or non-anthracycline regimen combined with trastuzumab ± pertuzumab.
combined with the above guidelines suggest that for patients with HER-2-positive breast cancer, anthracycline and taxane-based chemotherapy regimen should be given, and then trastuzumab or pertuzumab should be combined according to the patient's economic level and regional medical level.
Neoadjuvant therapy for patients with TNBC breast cancer
ASCO guidelines recommend TNBC breast cancer patients receiving anthracycline and purple shirt-based chemotherapy regimens, and carboplatin can be used as part of neoadjuvant chemotherapy regimen to increase the chance of obtaining pCR. The expert group of the Chinese Anti-Cancer Association recommends anthracycline sequential/combined taxanes as the preferred solution; in patients with higher tumor burden, especially when there is a clear BRCA1/2 mutation, a combination of platinum is recommended. The National Health Commission also recommends conventional plans containing anthracyclines and taxanes. It is also recommended that platinum can increase the likelihood of pCR as part of the scheme.
In combination with the above guidelines, for patients with TNBC breast cancer, neoadjuvant chemotherapy regimen containing anthracycline and purple shirt should be given. For platinum drugs, it is time to decide whether to use it in combination after weighing potential benefits and harms (such as with cardiac disorders). As for the application of PD1/PD-L1, since its relevant indications have not been approved in China, conventional combination of immune checkpoint inhibitors or only used in strictly designed clinical trials. Neoadjuvant treatment options for patients with HR-positive/HER-2-negative breast cancer
ASCO guidelines are recommended. For HR-positive/HER-2-negative patients, the timing of the surgery is not considered. Neoadjuvant chemotherapy can be given. For patients after menopause , neoadjuvant endocrine therapy can be given with aromatase inhibitor (AI) to increase local treatment options. For premenopausal patients, neoadjuvant endocrine therapy should not be given except for participating in clinical trials. The expert group of the Chinese Anti-Cancer Association recommends that neoadjuvant chemotherapy is the first choice for most patients at medium and high risk of recurrence. In specific patients in well-designed clinical trials, neoadjuvant endocrine therapy, preferred AI drugs (premenopausal combined with ovarian function inhibitors), fulvestrant, CDK4/6 inhibitors, or combinations with other endocrine therapy drugs are not recommended. The National Health Commission’s guidelines recommend that adjuvant chemotherapy should be recommended to advance to the neoadjuvant stage if there is a need for lowering the period or breast conservation.
combined with the above guidelines suggest that for patients with HR-positive/HER-2-negative breast cancer, the main focus should be on the selection of suitable groups. If preoperative treatment is required but is not suitable for chemotherapy, is temporarily not suitable for surgery, or does not require immediate surgery, you can consider neoadjuvant endocrine therapy alone; if there is a need for period-down or breast conservation, neoadjuvant chemotherapy ± endocrine therapy can be recommended.
Evaluation of Neoadjuvant therapy efficacy
Evaluation of Neoadjuvant therapy efficacy is divided into clinical evaluation and pathological evaluation. Clinical evaluation mainly includes physical examination , breast ultrasound, breast mammography and breast nuclear magnetism. With the continuous development of imaging technology, PET-CT and PET-MRI have also been used in the evaluation of breast cancer treatment [19-21]. One purpose of neoadjuvant therapy is to obtain drug sensitivity information in the patient's body to guide subsequent treatment. Therefore, it is especially important to have early normative assessments regardless of the tool or means used.
"Guidelines and Specifications for Breast Cancer Diagnosis and Treatment of Chinese Anti-Cancer Association (2021 Edition)" recommends that a detailed clinical examination should be conducted on the last day of the first cycle of treatment, that is, before the start of the second cycle of treatment, to have a preliminary understanding of the treatment response. Generally speaking, it is recommended to comprehensively evaluate the efficacy at the end of the second cycle of treatment, that is, before the third cycle of treatment. The evaluation results are based on the evaluation criteria for solid tumor efficacy evaluation (RECIST) version 1.1.
pathological examination is the gold standard for diagnosis, and its evaluation is more conducive to clinicians to judge the condition and formulate reasonable treatment plans. The current pathological evaluation in my country mainly includes the Miller-Payne evaluation system [22] and the residual tumor burden (RCB) evaluation system [23].
Based on clinical experience, we recommend using mammary ultrasound at least once a cycle and mammography every two cycles. Patients with financial conditions or who have multiple lesions can undergo breast nuclear magnetic evaluation before and after neoadjuvant chemotherapy.For neoadjuvant treatment, if the tumor is not retracted significantly or new tumors are new, a secondary puncture can be performed, and the treatment plan can be adjusted in time based on the results of immunohistochemistry .
Management of adverse events after neoadjuvant treatment
In the process of neoadjuvant treatment, in addition to standardized treatment plans, the accompanying systemic reactions also require strict attention. The occurrence of adverse events in neoadjuvant treatment mainly includes nausea, vomiting, bone marrow function inhibition and cardiotoxicity caused by chemotherapy. The symptoms such as nausea and vomiting caused by chemotherapy are intuitive, and in severe cases, it can lead to electrolyte disorders . For different risk regimens of vomiting, 5-HT3 receptor antagonists (such as ondansetron) may be used alone or in combination with dexamethasone and NK-1 receptor antagonists (such as aprepitane) [24]. The inhibition of bone marrow function caused by chemotherapy is manifested as a decrease in leukocytes 1-2 weeks after medication. For the deficiency of febrile neutrophils caused by different regimens, recombinant human granule cell stimulatory factor (rhG-CSF) and polyethylene glycol recombinant human granule cell stimulatory factor (PEG-rhG-CSF) can be prevented [25].
2021 "Guidelines for Standardized Management of Neutropenia Related to Tumor Chemoradiation and Chemotherapy in the Chinese Society of Clinical Oncology (CSCO) (2021)" provides an important basis for standardizing the management of neutropenia related to tumor treatment. The cardiac toxicity caused by chemotherapy mainly comes from anthracyclines. It is recommended to give prophylactic treatment to derrexon when using anthracyclines for the first time [26]. If necessary, please ask specialist for symptomatic treatment.
Summary
With the rapid development of economy and medical standards, the diagnosis and treatment level of breast cancer in my country has also made significant progress. However, the survival rate of breast cancer patients is still a certain gap with that of European and American countries. The problems that cause the above phenomena exist in many aspects, such as uneven distribution of medical resources, regional economic differences, and poor awareness of physical examinations among ordinary people. In addition, due to the characteristics of sporadic and recurrent COVID-19 epidemic, breast cancer patients, especially those receiving neoadjuvant treatment, have also been affected to varying degrees. Therefore, in this case, the standardized diagnosis and treatment of breast cancer is particularly important. Neoadjuvant therapy for breast cancer is a long-term, continuous process and a multidisciplinary treatment method. Therefore, during the diagnosis and treatment process, we must strictly follow the requirements of relevant guidelines and formulate reasonable and standardized individualized treatment plans for patients. At the same time, despite many factors that lead to delayed treatment, the management of adverse events cannot be ignored.
References
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