National guidelines for diagnosis and treatment of breast cancer 2022 in China (English version)

National Health Commission of the People’s Republic of China

Contents

1.Breast cancer screening

1.1 Recommendations for females at normal risk

1.1.1 Age 20?39 years old

1.1.2 Age 40?69 years old

1.1.3 Age ≥70 years old

1.2 Recommendations for females at increased risk

2.Diagnosis of breast cancer

2.1 Clinical manifestations

2.1.1 Breast lump

2.1.2 Nipple discharge

2.1.3 Skin changes

2.1.4 Abnormalities in nipple and areola

2.1.5 Enlarged axillary lymph nodes

2.2 Breast palpation

2.3 Imaging tests

2.3.1 Mammography

2.3.2 Breast ultrasound

2.3.3 Breast MRI

2.3.4 Positron emission tomography-computed tomography (PET-CT)

2.3.5 Bone scan

2.4 Laboratory tests

2.4.1 Blood chemistry

2.4.2 Tumor markers

3.Pathological diagnosis

3.1 Specimen type and fixation

3.1.1 Specimen type

3.1.2 Specimen fixation

3.2 Specimen dissection and gross description

3.2.1 Core needle biopsy specimen

3.2.2 Vacuum-assisted biopsy specimen (mammotome minimally invasive surgery specimen)

3.2.3 Lumpectomy specimen

3.2.4 BCS specimen

3.2.5 Mastectomy specimen

3.2.6 Sentinel lymph node biopsy (SLNB)

3.3 Classification,grading and staging

3.3.2 Histological grading

3.3.3 Staging

3.3.4 Immunohistochemistry,molecular pathology tests and quality control

3.3.5 Standardized pathology report

4.Differential diagnosis

5.Treatment

5.1 Principles

[3]參見萬明《白銀貨幣化與中外變革》，萬明主編:《晚明社會(huì)變遷問題與研究》，北京:商務(wù)印書館 2005年，第 144頁;吳承明:《市場(chǎng)·近代化·經(jīng)濟(jì)史論》，昆明:云南大學(xué)出版社 1996年，第 270頁。

5.1.1 Non-invasive breast cancer

5.1.2 Invasive breast cancer

5.2 Surgical treatment

5.2.1 Principles

5.2.2 Breast surgery

5.2.3 Surgery for axillary lymph nodes

5.2.4 Oncoplasitic and reconstructive breast surgery

5.3 Radiation therapy

5.3.1 Radiation therapy for early-stage breast cancer after BCS

5.3.2 Radiation therapy after modified radical mastectomy

5.3.3 Radiotherapy under special circumstances

5.4 Chemotherapy

5.4.1 Adjuvant chemotherapy

5.4.2 Neoadjuvant chemotherapy

5.4.3 Chemotherapy for advanced breast cancer

5.5 Endocrine therapy

5.5.1 Adjuvant endocrine therapy

5.5.2 Endocrine therapy for advanced breast cancer

5.6 Targeted therapy

5.6.1 Definition of HER2 positivity

5.6.2 Precautions

5.6.3 Postoperative adjuvant targeted therapy

5.6.4 Preoperative neoadjuvant targeted therapy

5.6.5 Targeted treatment for advanced HER2-positive breast cancer

6.Diagnosis and treatment flowchart

7.Follow-up

Breast cancer is the most common malignancy in females and presents a severe threat to females’ health.Currently,with comprehensive treatment modalities,the outcomes of breast cancer are among the best of solid tumors.A set of Chinese guidelines and recommendations are developed to standardize the clinical practice,to ensure the quality and safety of medical service,and to ultimately improve the prognosis of breast cancer patients.

1.Breast cancer screening

Breast cancer screening refers to the detection of precancerous lesions and infiltrating tumors at early stages in asymptomatic females with effective,convenient and economical methods.The ultimate goal of breast cancer screening is to lower the mortality of breast cancer patients through early detection and prompt treatment.

There are two kinds of screening:mass screening and opportunistic screening.Mass screening refers to screening organized by the local government for all females living or working in a community.Opportunistic screening refers to screening by health care providers as part of the outpatient consultation.

The age for breast cancer screening:we recommend females to start their first breast cancer screening at the age of 40 years old and earlier for females with higher risks.There is no recommendation for the age of population screening in China,and the age of 40?50 years for screening is recommended internationally.The current choices of age used for population screening are mainly for research purposes and cost-benefit analyses from randomized controlled trials are lacking.

1.1 Recommendations for females at normal risk

1.1.1 Age 20?39 years old

(1) Monthly breast self-examination.

(2) Clinical breast examination every 1?3 years.

1.1.2 Age 40?69 years old

(1) Opportunistic screening and mass screening.

(2) Mammogram and/or ultrasound every 1?2 years.

(3) Ultrasound is recommended for females with dense breast.

(4) Monthly breast self-examination.

(5) Annual clinical breast examination.

1.1.3 Age ≥70 years old

(1) Opportunistic screening (imaging examinations in cases with symptoms or suspicious physical examination findings).

(2) Monthly breast self-examination.

(3) Annual clinical breast examination.

1.2 Recommendations for females at increased risk

Annual screening should be started earlier (＜40 years) in females at increased risk for breast cancer.Magnetic resonance imaging (MRI) could be considered in addition to mammogram and ultrasound.

Increased risk is defined if females meet any of the following criteria:1) present genetic predisposition to breast cancer (see the criteria for genetic testing);2)diagnosis of lobular carcinomain situ(LCIS)/atypical hyperplasia;and 3) prior history of thoracic irradiation.

Potential hereditary breast-ovarian cancer syndrome is as follows referring to genetic consulting:

(1) KnownBRCA1/BRCA2mutation carrier in family.

(2) Breast cancer patients meeting any of the following criteria:1) early onset breast cancer (≤45 years);2) early onset breast cancer (≤50 years) and having one or more than one close family members diagnosed of early onset breast cancer (≤50 years),and/or having one or more than one close family members diagnosed of ovarian cancer/fallopian cancer/primary peritoneal cancer;3) early onset multiple primary breast cancer with the first diagnosis before the age of 50 years;4) two or more close family members diagnosed of breast cancer and/or ovarian/fallopian/primary peritoneal cancer;5) family member with male breast cancer;and 6) history of ovarian/fallopian/primary peritoneal cancer.

(3) Diagnosed as ovarian/fallopian/primary peritoneal cancer.

(4) Male breast cancer.

(5) With following family history:1) first/second-degree relative meeting any of the criteria above;or 2) having two or more than two third-degree relatives diagnosed of breast cancer (at least one relative ≤50 years) and/or ovarian/fallopian/primary peritoneal cancer.

2.Diagnosis of breast cancer

The diagnosis of breast cancer is based on clinical examination in combination with imaging,and confirmed by pathological assessment.

2.1 Clinical manifestations

Early-stage breast cancer is usually asymptomatic and often diagnosed after suspicious findings during physical examination or breast cancer screening.The followings are positive findings during physical examination.They are mostly seen in patients with advanced diseases.

2.1.1 Breast lump

Around 80% of breast cancer patients seek medical consultations for palpable lumps in breasts.The lumps are often accidentally found by patients themselves,often with irregular margins,and the surface of the lumps might be uneven.Most of the lumps are painless.

2.1.2 Nipple discharge

Nipple discharge refers to the secretion of unusual fluids such as blood,serum,breast milk or pus in females who are not pregnant or breast-feeding.Possible causes of nipple discharge including intraductal papilloma,fibrocystic breasts,mammary duct ectasia and breast cancer.Breast duct endoscopy should be conducted in patients with single-duct bloody nipple discharge.

2.1.3 Skin changes

A variety of skin changes can be found in breast cancer patients.Dipple sign is the most common lesion,caused by suspensory ligament of the breast (cooper ligament)invaded by tumors adhering to the skin.Peau d’orange can be observed when tumors block the dermal lymphatic vessels.Dimpling and satellite lesions caused by metastases.In the late stage of breast cancer,tumor cells infiltrate into the skin along lymphatic vessels,glandular ducts or fibrous tissues,forming skin satellite nodules.

2.1.4 Abnormalities in nipple and areola

Both retraction and protrusion of the nipple could be signs of breast cancer.Paget’s disease of the nipple can cause eczema/scaling in the skin around the nipple and areola.

2.1.5 Enlarged axillary lymph nodes

Palpable axillary masses are often the only symptom in patients with occult primary breast cancer on initial diagnosis.Apart from that,over 1/3 of breast cancer patients have metastases in axillary lymph nodes.In early stages the lymph nodes might just be enlarged and hardened but still movable.As diseases progress,several lymph nodes might merge and become adhesive to the skin.In advanced diseases,palpable lymph nodes can be found in the ipsilateral supraclavicular fossa and/or contralateral axilla.

2.2 Breast palpation

Before breast palpation,a detailed medical history including breast diseases in the past,marital and period status,and history of malignancy in the family should be collected.It is recommended that premenopausal females receive breast palpation after the period.

Females should stand upright or sit on a chair.Supine position is also acceptable for females with ptotic or large breasts.Before palpation,the examiner should first observe the breasts and look for abnormal signs.Always examine the“normal”breast before moving on to the“abnormal”breast.Use the pads of fingers and move in a systematic fashion so that all the tissues are palpated.Make sure to palpate the nipple and areolar regions and the axillae.Most of the masses can be found during palpation except some early-stage diseases.During palpation,look for abnormalities such as swelling in part of the breast,nipple discharge,nipple erosion,nipple retraction,skin dimpling,swelling in the areolar region and post-menopausal breast pains.

2.3 Imaging tests

2.3.1 Mammography

Mammography is the most important and fundamental tool in breast imaging.It is irreplaceable in detecting calcifications in breast tissues.However,its ability to detect abnormalities in dense breasts and masses close to the chest is limited.Mammography also exposes females to radiation,it is not recommended as the preferred option for young females.

The commonly used positions for mammography are mediolateral oblique (MLO) and craniocaudal (CC)positions.Other additional positions are considered when breast tissues are not adequately or completely shown,including lateromedial (LM),mediolateral (ML),medial craniocaudal (MCC),lateral craniocaudal (LCC),CLEO and cleavage position.Under certain circumstances,special techniques might be adopted for a clearer imaging.

Indications:For breast screening and diagnostic imaging.1) Screening in asymptomatic populations;2)further investigation of breast abnormalities detected by other methods;3) symptoms such as breast mass,partial breast swelling,abnormal nipple discharge,abnormal skin changes and localized breast pains;4) follow-up for females with benign breast diseases;5) follow-up for breast cancer patients receiving breast conserving surgery (BCS);6)follow-up for patients receiving breast reconstruction;and 7) guided biopsy.

For females under 40 years of age with average risk or no abnormal physical examination finding,mammography is not recommended as the preferred option.Mammography is typically not used in pregnant females.

2.3.2 Breast ultrasound

Breast ultrasound is applicable in females of all ages suspected of breast diseases.Breasts and axillary lymph nodes can be evaluated at the same time.Patients usually lie flat on the bed and the scanning area should cover the whole breast as well as the axilla.

Conventional breast ultrasound is sensitive in detecting breast lesions.A series of ultrasound parameters can be used to facilitate the differentiation between benign and malignant diseases.Ultrasound elastic imaging and contrast enhanced imaging might be useful in differential diagnosis of breast lesions.

Indications:1) Patients with symptoms (breast mass,abnormal nipple discharge,abnormal skin changes,etc.);2)screening in asymptomatic high-risk patients;3)complementary examination to mammograph;4) follow-up of benign breast diseases,breast cancer after surgery and postmenopausal females receiving hormone replacement drugs;and 5) guided biopsy.

2.3.3 Breast MRI

Compared to other imaging methods,breast MRI is more sensitive in detecting multi-center lesions and bilateral lesions.The relationship between the tumor and the chest wall and lymph nodes metastases can be shown at the same time.MRI may provide more reliable evidence for evaluating the disease and making surgery plans.However,its disadvantages cannot be neglected either.They include moderate specificity,high false-positive rate,inferiority in detecting microcalcifications.In addition,long examination time and high costs also limit its clinical use.So far it has not been recommended as the preferred option for breast evaluation.High-field strength equipment (above 1.5 T)and breast array coil are recommended,and patients should be positioned in a prone position.Breast MRI should include the sequences below:T1-weighted images (with and without fat-suppression),T2-weighted images (fatsuppression),diffusion-weighted imaging (DWI),peak enhancement (horizontal dynamic enhancement and sagittal scanning).

Indications:1) Unspecific results after mammography and breast ultrasound;2) preoperative staging and screening for contralateral tumors;3) evaluation of tumor response to neoadjuvant chemotherapy;4) evaluation of the primary tumor in patients with occult breast cancer and axillary lymph node metastasis;5) differential diagnosis between postoperative scarring and cancer relapse;6)evaluation of the residual disease in patients with positive margins after lumpectomy;7) evaluation of breast implants;8) screening in females with high risk;and 9) guided biopsy.

Contraindications:1) Implanted pacemaker or defibrillator,metallic clips and other metallic objects in the body which can be heated and/or moved by the magnetic field;2) allergy to Gadolinium chelates;3) claustrophobia;4) pregnancy;or 5) poor physical condition and unable to tolerate MRI.

2.3.4 Positron emission tomography-computed tomography(PET-CT)

The following recommendations are developed based on National Comprehensive Cancer Network (NCCN)guidelines,European Society for Medical Oncology(ESMO) guidelines,Japanese Breast Cancer Society (JBCS)guidelines and Chinese Anti-Cancer Association (CACA)guidelines.

Indications:1) Pretreatment staging for patients with clinically advanced diseases,unfavorable molecular tumor subtypes,or suspected to have distant metastases;and 2)suspected to have local relapse or metastases during follow-up.

Relative contraindications:1) Pregnant or breastfeeding females;2) patients with severe heart,liver,or kidney dysfunction or allergy to iodine-based contrast materials;3) patients with severe diseases,unable to lie flat for at least 15 min,patients with incontinence or claustrophobia;or 4) patients with increased intracranial pressure due to brain metastases.

2.3.5 Bone scan

Pretreatment staging for patients with invasive carcinoma:For patients with clinical stage I?IIB diseases,a bone scan might be ordered in cases of localized bone pain or elevated alkaline phosphatase levels to detect bone metastases.For patients with clinical stage III diseases,a bone scan or a NaF-PET-CT scan might be ordered to detect bone metastases.For patients with cancer relapses or clinical stage IV diseases,a bone scan or a NaF-PET-CT scan might be ordered to detect bone metastases.

However,if results from a previous FDG PET-CT indicate bone metastases which are shown both in PET and CT image,a bone scan or a NaF-PET-CT scan might no longer be needed.

Follow-up:When patients present with bone pains or elevated alkaline phosphatase levels,bone scans may be used to detect bone metastases.Screening for metastases is not recommended in patients without symptoms or signs indicating relapses.

2.4 Laboratory tests

2.4.1 Blood chemistry

No significant changes in early-stage diseases.

2.4.2 Tumor markers

Carbohydrate antigen 15-3 (CA15-3) and carcinoembryonic antigen (CEA) are commonly used for monitoring metastatic breast cancer.However,these tumor markers are low in both sensitivity and specificity,making them inappropriate for breast cancer screening and diagnosis.

3.Pathological diagnosis

Pathological analysis is fundamental to the diagnosis and treatment of breast cancer.In addition to accurate diagnosis,pathological analysis should also provide makers related to treatment options,prediction of therapeutic effects and prognoses.A clinician is required to provide complete and accurate clinical information,as well as adequate and standardized tissue specimens to the pathologist.

3.1 Specimen type and fixation

3.1.1 Specimen type

Specimens from core needle biopsy,vacuum assisted biopsy and various surgical resections are common breast specimen types (mammotome minimally invasive surgery,partial breast lumpectomy,BCS,simple mastectomy and modified radical mastectomy after neoadjuvant chemotherapy).

3.1.2 Specimen fixation

Core needle biopsy and resection specimens should be immediately fixed (within 1 h) with adequate 4% neutral formaldehyde for 6?48 h.Resection specimens should then be cut at 5?10 mm intervals.It is advisable to separate the adjacent tissue pieces with gauze or filter paper to ensure sufficient penetration and fixation at 12?72 h.

3.2 Specimen dissection and gross description

After the specimen is received,the first step is to carefully check the information of the specimen container and the pathological application form (the patient information,gender,age,ID number,specimen type and location,clinical diagnosis,submitter,etc.).

3.2.1 Core needle biopsy specimen

(1) Gross examination and description:The number of tissue samples,the size of each sample (including diameter and length) should be mentioned.

(2) Processing:All tissues are to be processed.Core needle biopsy specimens are not suitable for intraoperative frozensection examination.

3.2.2 Vacuum-assisted biopsy specimen (mammotome minimally invasive surgery specimen)

(1) Gross examination and description:Total size of the tissues should be mentioned.

(2) Processing:All tissues are to be processed.Vacuumassisted biopsy specimens are not suitable for intraoperative frozen-section examination.

3.2.3 Lumpectomy specimen

(1) Gross examination and description:Gross description should be carried out according to the surgeon’s orientation.If not clearly marked,pathologists should contact the surgeon.If the specimen has skin on it,the size of the skin should be measured.Record the location and appearance of the tumor or suspected lesions.Record the slice information corresponding to each specimen.

(2) Intraoperative frozen section specimen:The specimen is cut at 5 mm intervals along the long axis.If a clear mass is present,it is directly sectioned.For specimens contain calcifications,preoperative X-ray information or the position of the localization wire should be used to indicate the location of dissection.If no clear mass is present,the suspected lesion is dissected.

Paraffin embedded specimens:If the maximum diameter of the tumor or suspicious lesion is less than or equal to 5 cm,it should be cut at no more than 1 cm intervals.If the maximum diameter is greater than 5 cm,it should also be cut at 1 cm intervals.If a previous diagnosis of ductal carcinomain situ(DCIS) exists,it is recommended that all tissues be processed.

3.2.4 BCS specimen

(1) Gross examination and description

1) Gross description should be carried out according to the surgeon’s orientation.If the specimen is not clearly marked,pathologists should contact the surgeon.

2) Measure the size of the specimen.If the specimen has skin on it,the size of the skin should be measured.

3) The specimen should be correctly placed according to the surgeon’s orientation.It is recommended that different colored ink be applied to mark the margins of the specimen(anterior,posterior,superior,inferior,medial and lateral).After the ink is slightly dry,remove excessive ink.

4) The specimen is cut at 3?5 mm intervals from the surface to the base,and the orientation and sequence of the sectioned tissues are maintained.

5) Carefully look for the lesion and measure the size of the lesion in three dimensions;if it is a specimen after chemotherapy,measure the size of the tumor bed;if it is a post-resection specimen,measure the size of the residual cavity and search for residual lesions.

6) Measure the distance between the tumor,the tumor bed or the residual cavity from each margin and observe the nearest margin.

7) Record the information of each tissue and the corresponding slices.

(2) Dissection

1) Margin

There are two main methods for obtaining the margins of a breast conserving specimen:radial sections perpendicular to the margin and shave sections of the margin.Regardless of the methods,it is recommended that ink of different colors be applied to the six margins.Margin status should be clearly defined in the pathology report.“Positive margin”refers to the presence of DCIS or invasive carcinoma on ink.The definition of“negative margin”is not consistent,in most guidelines and consensus,“no tumor on ink”is used to define a“negative margin”.It is recommended the actual distance between the margin and the tumor be reported.

Radial sections perpendicular to the margin:According to the orientation marked by the surgeon,the specimen is cut into a plurality of slices at 5 mm intervals.Describe the size of the tumor,the location of the tumor,and the distance from the tumor edge to each margin.The margins close to the tumor are sectioned together with the tumor.The advantage of“radial section”is that the distance between the tumor edge and the margin can be accurately measured.The disadvantage of the method is the heavy workload.

Shave sections of the margin:Tissues form all six margins are separated from the specimen and all the margin tissues are to be processed.The advantage of the method is that the amount of tissue is small,and the entire margin can be microscopically observed.The disadvantage is that the distance between the tumor edge and the margin cannot be accurately measured.

2) Tumor and surrounding tissues

The method of dissection is the same as previously described in that of intraoperative-frozen section specimens.

3) Additional margins

If the margin is positive,additional margin tissues should be examined.If the surgeon has oriented additional margin tissues,it can be inked and continuously cut perpendicularly to the margin surface.If the specimen is small,all tissues are to be processed.

3.2.5 Mastectomy specimen

(1) Gross examination and description

1) In order to identify the quadrant in which the tumor is located,orientation of the specimen is important.Modified radical mastectomy specimen can be correctly positioned by acknowledging the axillary tissues.The orientation of simple mastectomy specimen is based on the surgeon’s mark.It is recommended that the base of the specimen should be inked.

2) Measure the size of the entire specimen.Describe the appearance of the skin,the presence of skin abnormalities should be mentioned (surgical incisions,scars,erythema,edema,etc.).

3) The nipple is cut horizontally to observe the section of the lactiferous duct,and then the nipple is cut perpendicular to the surface.Describe the appearance of the nipple and areola.

4) The specimen is cut perpendicular to the base.

5) Look carefully for lesions;record the location and the characteristics of the tumor (texture,color,margin,etc.).If a clear mass is present,measure the size of the mass in three dimensions;if it is a specimen after chemotherapy,measure the size of the tumor bed;if it is a post-resection specimen,measure the size of the residual cavity and search for residual lesions.Measure the distance between the tumor/tumor bed/residual cavity and the nearest surface margin/base margin.

6) Describe the normal tissue around the tumor.

7) After the axillary tissue is removed from the specimen,at least 15 lymph nodes should be found.Count the total number of lymph nodes,measure the maximum diameter of the lymph nodes,and it should be mentioned if lymph nodes become matted or adhere to surrounding tissues.

(2) Dissection

Primary tumor and surgical cavity:The method of dissection is the same as previously described in that of intraoperative-frozen section specimens.The nipple,the skin closest to the tumor,the basal margin closest to the tumor,and a piece of representative breast tissue from each quadrant should be sectioned as well.

Axillary lymph nodes:If the lymph nodes are grossly negative,the entire lymph nodes are to be examined.If the lymph nodes are grossly positive,the node is cut along the maximum diameter for examination.The connective tissues around the node should also be examined to identify possible tumor invasion outside the lymph node.

3.2.6 Sentinel lymph node biopsy (SLNB)

SLNB has replaced traditional axillary dissection in some breast cancer patients.Patients with negative SLNBs might avoid axillary dissections.

(1) Definitions of SLNB metastases

1) Isolated tumor cells (ITC):The diameter of the tumor in the lymph node ≤0.2 mm or the number of tumor cells on a single slice ＜200.American Joint Committee on Cancer(AJCC) stages ITC as pN0(i+).At present,most guidelines consider ITC not clinically significant,and it is recommended that ITC be treated as negative axilla.

2) Micrometastasis:The maximum diameter of the tumor in the lymph node ＞0.2 mm but ≤2 mm.AJCC stages micrometastasis as pN1mi.ITC is essentially different from micrometastasis,the former is pN0 and the latter is pN1.The differential diagnosis of ITC and micrometastasis is very important.It is recommended that sentinel lymph nodes at 2 mm intervals be cut to detect possible micrometastasis.

3) Macrometastasis:The maximum diameter of the tumor in the lymph node ＞2 mm.

(2) Intraoperative examination

The main purpose of intraoperative examination of SLNB is to detect metastasis,thereby avoiding performing axillary lymph node dissection (ALND) in a second procedure.However,intraoperative evaluation of SLNBs is controversial.

1) Intraoperative imprint cytology:Cut the lymph node at 2 mm intervals,carefully check for macrometastases on each slice,and imprint cytology is performed for each section.Pap and hematoxylin eosin (HE) staining are recommended.The advantage of imprint cytology is the preservation of the entire lymph node tissue.It is a cheap,simple and time-saving process.The major disadvantage is that imprint cytology is difficult to identify scattered cancer cells (such as lobular carcinoma).It has good diagnostic specificity,but the sensitivity is affected by many factors.

2) Intraoperative frozen section:Cut the lymph node at 2 mm intervals,carefully check for macrometastases,then frozen section each slice for pathological evaluation.The advantage of frozen section is its good diagnostic specificity and it can avoid unnecessary ALN dissection due to false positive results.The disadvantages include tissue loss,timeconsuming,high cost,and technical difficulty in assessing fatty lymph nodes.

(3) Paraffin embedded evaluation

Postoperative paraffin embedded section is the“gold standard”of diagnosis.However,there is no consensus on how to cut the lymph nodes and what the intervals are,our recommended scheme:1) Cut the lymph nodes at of 2 mm intervals;2) All tissue slices are paraffin embedded in seperate blocks;and 3) Cut at least one slice per block and it is recommended that 6 slices at 150?200 μm intervals be cut.

3.3 Classification,grading and staging

3.3.1 Histological classification

Histological classification is mainly based on the World Health Organization (WHO) breast cancer classification and some histological types need to be determined by immunohistochemistry.

Accurate histological classification of invasive breast cancer is crucial to individualized treatment.The NCCN guidelines recommended less intense treatment strategies for tumors with good prognoses (such as tubular carcinoma and mucinous carcinoma).Meanwhile,more intensive treatment strategies were recommended for tumors with poor prognoses (such as inflammatory breast cancer).Medullary carcinoma used to be considered to have a good prognosis,but current studies have shown that the risk of metastasis is comparable to other invasive breast carcinomas,and the diagnostic reproducibility is poor among different examiners.Therefore,the NCCN guidelines recommend that patients with medullary carcinoma should receive the same treatment as patients with invasive ductal carcinoma (IDC).Some special types of breast cancer have special clinical features.For instance,invasive micropapillary carcinoma is more likely to have lymph node metastasis.For mixed tumor types,it is recommended that the proportion and molecular biomarkers for each component be reported separately.

3.3.2 Histological grading

(1) Invasive breast cancer

Histological grade is an important prognostic factor.The modified Scarff-Bloom-Richardson grading system is widely used.According to the system,the ratio of duct formation,cell atypia and mitotic count are the three factors each independently assessed and given a score from 1 to 3 points.Invasive breast cancers are divided in to grade 1,2 and 3 by calculating the sum of three scores.

The extent of ductal formation for the whole tumor needs to be assessed at low-power fields.When evaluating tubules and glands,only structures exhibiting clear lumina surrounded by polarized cells are counted,expressed as percentage of glandular/tumor area.

Nuclear pleomorphism is assessed by reference to the regularity of nuclear size,shape and nucleolar size of normal mammary epithelial cells.When there is a lack of normal cells,lymphocytes can be used as a reference.When the nuclei are similar to the surrounding normal cells in size and shape,and the chromatin is evenly distributed,1 point is assigned;when the nuclei are larger than normal cells,the shape and size show moderate atypia,and single-nucleolus is seen,2 points are assigned;when the size of the nuclei shows significant atypia,the nuclei are significant,and multiple nucleoli are seen,3 points are assigned.

Pathologists only count definite mitotic figures,hyperchromatic nuclei and nuclear debris are not included.Choose areas with the most mitotic activities for mitotic count,usually near the edge of the tumor.If there is heterogeneity,regions exhibiting a higher frequency of mitoses should be chosen.

(2) Grading of DCIS

Low grade:Composed of small,monomorphic cells,growing in arcades,micropapillae,cribriform or solid patterns.The nuclei are of uniform in size and have inconspicuous nucleoli;mitotic figures are rare.

Intermediate grade:Morphological manifestations between low-grade and high-grade DCIS.Composed of cells show mild to moderate variability in size and shape.Coarse chromatin,prominent nucleoli,mitoses and comedo necrosis may be present.

High grade:Composed of highly atypical cells most often proliferating in solid,cribriform or micropapillary patterns.Nuclei are pleomorphic,poorly polarized,with irregular contours and distribution,coarse,clumped chromatin and prominent nucleoli.Mitotic figures are common.Abundant necrotic debris often present in the duct lumina.However,comedo necrosis is not obligatory.Even a single layer of highly atypical cells lining the duct in a clinging fashion is sufficient for the diagnosis of highgrade DCIS.

3.3.3 Staging

Tumor size,the involvement of chest wall or the overlaying skin,lymph node metastasis,and distant metastasis are factors that determine the stage of the breast cancer.Correct staging is fundamental to individualized treatment.The eighth edition AJCC staging manual has described the rules for measuring tumor size in details.Tumor size can be measured by multiple ways,such as clinical palpation,imaging assessment as well as gross and microscopic measurements by the pathologist.Only the size of the invasive carcinoma is meaningful in tumor staging.Only microscopic measurement is accurate,because other methods cannot distinguish between invasive and intraductal components.If the invasive component is large and cannot be completely embedded with one block,it should be measured grossly.If the invasive component can be completely embedded with one block,then tumor size is determined microscopically.(1) If both invasive andin situcomponents are present,the size should be based on the invasive component.(2) In cases ofin situcarcinoma with microinvasion,the maximum diameter of microinvasion should be measured.If multi-microinvasions are present,it should be mentioned in the report and the size of the largest microinvasion should be measured.(3) If two or more tumors can be grossly identified in the same quadrant,multifocal tumors should be reported by the pathologist and the size of each tumor focus should be measured separately.(4) If more than two tumors can be grossly identified in different quadrants,multicentric tumors should be reported by the pathologist,and the size of each tumor primary should be measured separately.(5) If the tumor consists entirely of DCIS,the extent of tumor should be measured as much as possible.Lymph node metastasis is an important factor in determining treatment and prognosis.When the number of lymph node metastases comes close to the threshold (such as 1,3 and 10 metastasized nodes),it should be carefully checked to determine the accurate pN stage.

For patients who received neoadjuvant treatment,the posttreatment tumor staging should be determined by incorporating clinical,imaging and pathological information.

3.3.4 Immunohistochemistry,molecular pathology tests and quality control

Estrogen receptor (ER),progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2)examination should be performed for all invasive breast cancers.HER2 (2+) cases should be further tested byin situhybridization.ER and PR status identify patients that benefit from endocrine therapy.They are helpful when it comes to predict prognosis.The staining intensity and the percentage of ER/PR positive cells must be reported.Current definition of ER/PR positivity is ≥1% of tumor cells are stained positive.HER2 status is used to identify candidates for HER2 targeted therapy and to predict prognosis.HER2 positivity is defined by more than 10% of cells showing strong membrane staining (3+),and/orin situhybridization detectsHER2gene amplification (single copyHER2gene ＞6 or HER2/CEP17 ratio ＞2.0).

Ki-67 index also plays an important role in selecting treatment options and predicting prognosis.Ki-67 should be performed for all invasive carcinomas,and the percentage of Ki-67 positive cells should be reported.There is currently no consensus on the Ki-67 reporting system.Our recommendation is that the whole slice be evaluated under a low-power field to determine whether the positive cells are uniformly distributed.

If the positive cells are uniformly distributed,three or more high-power fields are to be randomly counted,and an average Ki-67 index is obtained.

If the positive cells are unevenly distributed,a prominent“hot spot”of Ki-67 index may exist.(1) If the hot spot appears at the junction of tumors and normal tissues,and the Ki-67 index was relatively low within the tumor,it is recommended that the Ki-67 index in 3 or more highpower fields should be counted in the tumor margin area;(2) If the hot spot appears within the tumor,the Ki-67 index of the whole slice can be evaluated on average 3 or more high-power fields including the hot spot area should be selected.When the Ki-67 index is within the critical range of 10%?30%,it is recommended that more than 500 invasive carcinoma cells should be evaluated as much as possible to improve the accuracy.

Laboratories that carry out immunohistochemistry and molecular pathology tests should establish complete and effective internal quality controls.Units that do not have adequate facilities or equipments should have the tests done in qualified laboratories.

Qualified laboratories should have the following conditions:

(1) A complete Standard Operation Procedure (SOP)should be established and strictly followed.

(2) Technicians and pathologists engaged in immunohistochemistry and molecular pathology tests should receive proper trainings and qualification assessments.

(3) External quality control can be achieved by participating in external quality control activities.The positive and negative coincidence rate of external quality control should be over 90%.The recommended frequency of such external quality control activities are 1?2 times per year.

3.3.5 Standardized pathology report

A standardized pathology report includes complete information related to treatment and prognosis of the carcinoma (tumor size,histological type and grade,existence of DCIS,vascular invasion,margin status,lymph node status,etc.).ER,PR,HER2 and Ki-67 results should also be included.For posttreatment specimens,treatment response should be reported.For DCIS,nuclear grade(low,intermediate or high),necrosis (comedo or spotty necrosis),margin status and ER/PR expression should be reported.Benign lesions adjacent to the cancer should be clearly stated.The pathology report of a BCS specimen should indicate the distance from the edge of the tumor to the nearest margin.Lymphovascular invasion needs to be differentiated from lacunar space caused by tissue contractions.It is more reliable to check for lymphovascular invasion around the tumor.

4.Differential diagnosis

Breast cancer needs to be differentiated from hyperplasia,fibroadenoma,cysts,primary mammary lymphoma and metastasis of malignant tumors.In the differential diagnosis of breast cancer,detailed medical history,careful physical examination and imaging examinations are required.Then cytological and/or pathological examinations are required to confirm the diagnosis.About 80% of breast cancers can be found by palpation.The diagnosis can be confirmed by needle biopsy.However,for impalpable tumors,image tests may be necessary to guide needle biopsy,and wire localization may also be necessary to locate and biopsy lesions.

A small number of breast cancer patients presented with nipple discharge need to be differentiated from hyperplasia,ductal dilatation,milk retention,intraductal papilloma and papillomatosis.Smear cytology may be used to find cancer cells.Ductalscopy may be useful in finding intraductal tumors.

5.Treatment

5.1 Principles

A multi-disciplinary approach should be adopted to improve survival and quality of life.

5.1.1 Non-invasive breast cancer

(1) LCIS

Females with LCIS tend to have a slightly higher risk of developing invasive breast cancer.And that is more likely to happen over the long term.A lot of the cases are multicentric and bilateral.

LCIS usually does not cause symptoms.If calcifications,lumps or tissue distortions are detected by mammography,stereotactic core needle biopsy or wire localized biopsy may be necessary to confirm the diagnosis.In cases core needle biopsy found classic LCIS,regular imaging follow-up may be considered.However,in cases core needle biopsy showed pleomorphic LCIS or other suspicious findings,a surgical biopsy may be necessary to rule out DCIS and invasive cancer.

For premenopausal females with LCIS,tamoxifen for 5 years is recommended after wide local excision.For postmenopausal females,tamoxifen or raloxifene may be given to lower the risk of breast cancer.Mastectomy may be considered if pleomorphic LCIS cannot be ruled out and breast reconstruction is planned.

(2) DCIS

DCIS is widely believed to be the precursor to IDC.If left untreated,some DCIS might eventually progress to IDC.The majority of asymptomatic DCIS is discovered by screening mammography with calcification being the most common finding.A core needle biopsy or wire-localized biopsy is required to establish diagnosis.However,when the diagnosis of DCIS is made by core needle biopsy,a surgical biopsy is necessary to rule out IDC.

1) Wide local excision and whole breast radiation.

2) Mastectomy.The necessity of SLNB should be evaluated if the patient is offered the choice of breast reconstruction.For patients with pure DCIS,ALND is not recommended.

3) Under the following circumstances,tamoxifen for 5 years is indicated to reduce the risk of contralateral breast cancer.A) ER-positive DCIS after BCS and radiation therapy;and B) DCIS after mastectomy,but the risks and benefits must be carefully evaluated.

5.1.2 Invasive breast cancer

(1) BCS and radiation.

(2) Mastectomy with ALND (modified radical mastectomy).Breast reconstruction should be considered.

(3) Mastectomy with SLNB.Breast reconstruction should be considered.

(4) Elderly breast cancer patients may consider wide local excision or total mastectomy based on patients’ medical conditions.ER and/or PR positive patients should be given endocrine therapy.SLNB should be considered as appropriate.

5.2 Surgical treatment

5.2.1 Principles

The breast as well as the ipsilateral axilla need to be considered when planning surgery.Surgery for the breast includes BCS and mastectomy.Surgery for axilla includes SLNB and ALND.The selection of different surgical procedures should take TNM stage and patients’ physical condition into consideration.

5.2.2 Breast surgery

(1) Mastectomy

Indications:Early-stage breast cancer and some locally advanced breast cancer without contraindications;the patient has no intention to preserve her breast or BCS is not applicable;and some locally advanced breast cancer patients or patients with existing distant metastases who are down-staged by systemic therapy are also candidates for mastectomy.The Halsted mastectomy removes the whole breast and pectoral muscles at the same time.Due to large surgical trauma and high complication rate,the Halsted mastectomy has been replaced by modified radical mastectomy.Usually the fascia overlying the pectoralis major muscle is removed during mastectomy but some believe that the fascia may be kept intact when patients undergo immediate breast reconstructive surgery.

Currently,modified radical mastectomy is being replaced by skin sparing mastectomy plus immediate breast reconstruction which offers similar survival but better cosmetic outcome.Nipple sparing mastectomy is also gaining acceptance but long-term follow-up data are still lacking.

(2) BCS

Indications for BCS should be strictly observed.Institutions that carry out BCS should have the equipments and techniques for histological examination of the BCS specimen in order to ensure negative surgical margins.Equipments for postoperative radiotherapy are also necessary.

The aim of BCS is to remove the tumor entirely without affecting breast appearance.The patient’s wishes should always be considered when deciding treatment.Age alone should not be a determining factor in selecting surgical strategy,however females less than 35 years may have increased risk of recurrence that needs to be considered.Conversely,one who has difficulty in complying with six weeks of radiation treatments may be the candidate for mastectomy.

Absolute contraindications:When two or more primary tumors are located in different quadrants of the breast or diffuse cancerous microcalcifications are present,BCS is not appropriate.Previous breast irradiation history,T4 tumor that involves the skin or the chest wall,inflammatory breast cancer and repeated positive surgical margins are also contraindications to BCS.Breast irradiation cannot be given during pregnancy,but it may be possible to perform BCS in the third trimester and administer irradiation after delivery.

Relative contraindications:Most radiation oncologists consider a history of collagen vascular disease a relative contraindication because the poor vasculature in the skin leads to unacceptable cosmetic results.Tumor size is not an absolute contraindication,but the presence of a large tumor in a small breast treated with adequate margins might result in an unwanted cosmetic appearance.

5.2.3 Surgery for axillary lymph nodes

Lymph node status remains one of the strongest predictors of long-term prognosis in early-stage breast cancer,providing information that is important for tailoring postsurgical treatment.Because imaging techniques have limited sensitivity,the axillary nodes must be explored surgically.

(1) SLNB

SLNB has replaced ALND as the standard surgical procedure for cN0 patients with early-stage breast cancer.It considerably reduces surgical morbidity,without affecting diagnostic accuracy.SLNB is based on the concept that a tumor-free SLN excludes metastatic involvement of the other axillary nodes.NCCN breast cancer guidelines recommend SLNB for females with clinical negative lymph nodes to detect possible nodal metastases.Lymphatic mapping is necessary before SLNB,commonly used tracers include blue dye and radiotracer.SLNB can accurately stage the axilla.Patients with negative SLNs can avoid ALND thus reducing edema and other complications of the upper limb.Currently,ALND will be performed if sentinel lymph node is positive.

(2) ALND

Indications:1) Fine needle aspiration or core needle biopsy proved axillary lymph node metastases;2) SLN-positive patients who do not meet the ACOSOG Z0011 criteria(females with T1?2 early-stage breast cancer and less than or equal to 2 positive SLNs,who will receive conservative surgery and whole-breast radiotherapy);3) recent insufficient ALND;4) failure of SLNB;5) patients with non-sentinel lymph node metastases;6) locally advanced invasive breast cancers (T4) or inflammatory breast cancer patients;and 7) axillary recurrence after SLNB.

A level I axillary dissection refers to extirpation of tissues lateral to the lateral border of the pectoralis minor muscle,a level II dissection refers to the removal of tissues between the medial and lateral borders of the muscle,and a level III dissection indicates tissue dissection medial to the muscle’s medial border.Most surgeons generally dissect levels I and II of the axilla.If there are palpable lymph nodes lateral to the pectoralis minor muscle,then the pectoralis minor muscle is divided and a level III dissection is performed.The minimum requirement for ALND is to remove 10 lymph nodes,so as to ensure the status of axillary lymph nodes can be truly reflected.

5.2.4 Oncoplasitic and reconstructive breast surgery

The standard modified radical mastectomy can lead to breast defect and has a typical horizontal scar across the chest wall.In some cases,in order to ensure an oncological safe resection,BCS also may generate unsatisfying cosmetic results.Oncoplasitic and reconstructive breast surgery can reduce anxiety and thereby improve the quality of life,and it has become an indispensable part of the breast cancer treatment.Nowadays,more and more surgeons have accepted the idea and mastered the technique,the number of reconstructive surgeries in China is increasing.

The oncological safety of reconstructive surgery in breast cancer patients has been confirmed.The timing and method of reconstructive surgery do not affect survival outcomes

Normally,breast reconstructive surgery is not in conflict with adjuvant chemotherapy.Chemotherapy will be delayed only when serious complications,such as infection and wound dehiscence,occur after immediate reconstructive surgery.Besides this,adjuvant chemotherapy will not increase the incidence of postoperative complications,will not affect the cosmetic outcome of reconstructive surgery,and will not impair wound healing.However,neoadjuvant chemotherapy might increase the incidence of infection and flap necrosis after reconstructive surgery.Breast reconstructive surgery should not be offered to patients during the course of chemotherapy due to declined immune function and anti-infection ability.

Neither autologous flap reconstruction nor implant reconstruction is a contraindication to radiotherapy.However,breast reconstruction does increase the technical difficulty of postoperative radiotherapy field design.The irradiated reconstructed breasts often show an unsatisfactory aesthetic outcome,which can be evident even after a long time.And the aesthetic appearance and patient satisfaction may be worse than patients with nonirradiated breasts.

The principles of reconstructive breast surgery:

(1) Oncological safety must be put first.Breast reconstructive surgery should not delay adjuvant therapy.

(2) Breast reconstructive surgery is an integral part of the therapeutic plan in breast cancer.The doctor is obliged to inform the patients that they have the right to choose reconstructive surgery.

(3) On the premise of oncological safety,the surgeon should preserve the skin,the subcutaneous tissues and other important aesthetic structures (such as the inframammary fold) as much as possible to allow satisfactory reconstruction of the shape and size of the breasts.

(4) The treatment of breast cancer should be carried out by a multidisciplinary team,and members from different departments (radiology,breast surgery,plastic surgery,imaging,pathology,psychology,nuclear medicine and immunology) work together.

Preoperative evaluation before breast reconstructive surgery:Important factors in assessing whether patients are suitable for breast reconstruction and determining the optimal technique include assessment of a patient’s general health,the body habitus,the size and shape of the ipsilateral and counter lateral breasts and patient preference.The doctor should combine the above conditions to develop a surgical plan with minimal trauma,low cost,low rate of complications and good cosmetic results.

Absolute contradictions for breast reconstructive surgery:Stage IV breast cancer;recurrent breast cancer;patient during the course of chemotherapy/radiotherapy,or within six months after radiotherapy.

Relative contradictions:For patients who have a history of previous radiotherapy and for those postoperative radiotherapy is planned,the timing and surgical procedure for breast reconstruction should be carefully selected.Severe obesity,smoking history,serious medical diseases and peripheral vascular diseases are the most important factors associated with postoperative complications.

Breast reconstruction may require a series of surgeries before a desirable cosmetic result can be achieved.Immediate breast reconstruction is an increasingly appealing option offering females the option of waking up after their mastectomy with a reconstructed breast.This has obvious psychological advantages,and patients who request immediate reconstruction are usually pleased with this decision and the outcomes.

Types of breast reconstructive surgery:Types of breast reconstructive surgery include reconstruction with prosthesis,autologous flap reconstruction,fat grafting,etc.The most common flaps for breast reconstruction include latissimus dorsi (LD) flap,transverse rectus abdominis muscle (TRAM) flap,deep inferior epigastric perforator(DIEP) flap,etc.

Follow-up for patients after breast reconstructive surgery:The follow-up of patients after breast reconstructions should start after the surgery and continue for more than 5 years.Follow-up should be performed regularly according to the type of breast reconstructive surgery.During follow-up,besides regular checks for any possible cancer recurrence,breast shape and symmetry,incision scar,donor site blood supply,prosthetic integrity,capsule contracture and other complications should also be observed.And if possible,changes in patients’psychological status and quality of life should be observed as well.

5.3 Radiation therapy

5.3.1 Radiation therapy for early-stage breast cancer after BCS

(1) Indications

Generally,all patients underwent BCS require radiation.Under special circumstances (patient over 70 years old,tumor smaller than 2 cm,lymph node negative,or ER positive),the omission of radiotherapy may be considered.

(2) Radiation field

1) Preliminary studies of accelerated partial breast irradiation (APBI) suggest that rates of local control in selected patients with early-stage breast cancer may be comparable to those treated with standard whole breast radiation therapy.

2) For pN0 patients who underwent BCS,the target includes the whole breast.

3) For patients with micrometastases in SLNs,or 1?2 positive SLNs,treated with SLNB but not ALND,high tangents (cranial tangent border ≤2 cm from humeral head)should be considered.Attention should be paid to setting the low and middle axilla and the whole breast as an integrated target area for delineation and irradiation,if intensity-modulated radiotherapy (IMRT) technique is used.For patients who do not meet this criteria,radiation field should include breast,SCV and axillary lymph nodes.4) In order to minimize the risk of recurrence,regional nodal irradiation is recommended for patients who have undergone ALND with 1?3 positive lymph nodes,and regional nodal irradiation can be avoided for patients with low risk of recurrence.Irradiation of the affected supraclavicular and infraclavicular regions is recommended,and irradiation of the internal breast region is determined by an individual basis.The overlap of risk factors such as young age,negative hormone receptor (HR),extensive vascular thrombosis,primary site in the medial/central quadrant,and high histologic grade may increase the importance of regional nodal irradiation.

5) For patients with more than 4 metastatic lymph nodes after ALND,the whole breast and the paraclavicular field should be irradiated (with attention paid to ensure cardiopulmonary safety).

6) Internal breast irradiation is controversial and is recommended for patients with the following conditions:a)≥4 lymph node metastases after ALND;b) primary tumors in the inner quadrant or central regions with axillary lymph node metastases;c) age ＜35 years with axillary lymph node metastases;and d) diagnosis of internal breast lymph node metastasis at the time of initial diagnosis or pathologically confirmed internal breast lymph node metastasis without internal breast lymph node dissection.Modern precision radiation techniques are recommended for internal breast irradiation in order to accurately assess the dose of radiation to normal tissues such as the heart,and to control the risks of cardiac-related injury.

7) Patients with complete ALND do not need prophylactic irradiation.Axillary irradiation can be used for patients with a high risk of axillary lymph node recurrence,but the risk of tumor recurrence needs to be weighed against the risk of increased lymphedema with radiotherapy.The risk factors include:a) Axillary node dissection was judged to be incomplete (based on the patient’s preoperative axillary tumor load,intraoperative finding of lymph node adhesion to surrounding blood vessels,or findings of axillary examination and imaging before radiotherapy);b) extraperipheral lymph node invasion;c) a high number of axillary lymph node metastases and a high percentage of lymph node positivity;and d) total number of axillary lymph nodes ＜10.However,the low number of axillary lymph nodes may be due to inadequate surgical clearance or inadequate pathology sampling,and communication between the surgeon and pathologist is necessary.

8) For patients treated with whole breast radiotherapy,tumor bed boost is recommended for patients who meet the following criteria:a) For invasive breast cancer:any grade if age ≤50 years,or high grade if age 51?70 years,or with positive margins;and b) For DCIS:age ≤50 years,high-grade tumor,close margins (＜2 mm) or positive margins.Tumor bed boost may be spared in patients with low recurrence risk:a) For invasive breast cancer:age ＞70 years,hormone receptor positive,low to intermediate grade with adequate negative margins (≥2 mm);and b) for DCIS:age ＞50 years,detected by screening,tumor size ≤2.5 cm,low to intermediate grade,and adequate negative margins (≥3 mm).For patients who do not meet the above criteria,individualized decision should be made based on balancing between oncological safety and cosmetic outcomes.

(3) Radiation technology

Radiation therapy after lumpectomy can be performed by using three-dimensional (3D) conformal radiotherapy,fixed field radiotherapy or volumetric arc radiotherapy.Regardless of the techniques used,it is recommended that the target volumes should be contoured with CT-based treatment planning,so as to accurately evaluate the dose distribution of the target volumes and the organs at risk.The outer contour of the ipsilateral breast and the surgical scar should be marked with lead wire to facilitate the determination of the total breast and tumor bed replenishment range.To further reduce dose to organs at risk,particularly heart and lung,respiratory control techniques,including deep inspiration breath-hold and prone positioning,are recommended.

Compared with two-dimensional (2D) radiotherapy,3D conformal and IMRT can improve dose homogeneity of the target volume,spare normal tissues,and resolve the problem of the radiation field connection between breast and regional lymph nodes，especially in those with larger breasts and need irradiation for regional lymph nodes,at the cost of increased complexity of the radiation plan.It is recommended that the choice of radiation techniques should be individualized.

Boost after breast conservation can be delivered using intraoperative radiotherapy,interstitial brachytherapy,electrons or external photons irradiation.Marking the tumor bed with clips is recommended to provide a reference for tumor bed.

(4) Radiation dose and segmentation mode

The recommended radiation dose of whole breast ±regional lymph nodes is 50 Gy/2 Gy/25 f.External beam irradiation of tumor bed can be sequentially applied after total breast irradiation (10?16 Gy/2 Gy/5?8 f).For an experienced team,simultaneous irradiation of the tumor bed is possible (60 Gy/2.4 Gy/25 f).For patients with whole breast irradiation,hypofractionated radiotherapy is also recommended:40 Gy/15 f or 42.5 Gy/16 f.For an experienced team,43.5 Gy/15 f/3 w can also be used.Sequentially applied after whole breast hypofractionated irradiation,the external beam radiation for tumor bed could use conventional fraction (10?16 Gy/2 Gy/5?8 f) or hypofraction (10 Gy/4 f).Sequential hypofractionated boost can also be considered (8.7 Gy/3 f).Clinical research on simultaneous hypofractionated boost is encouraged,for example:49.5 Gy/15 f.

For an experienced team,hypofractionated irradiation could be applied to patients undergoing whole breast +regional lymph nodes irradiation at the same dose of hypofractionated whole breast irradiation.

(5) APBI

Preliminary studies of APBI suggest that rates of local control in selected breast cancer patients with low recurrence risk may be comparable to those treated with standard whole breast radiation therapy.Patients are currently encouraged to participate in clinical trials investigating partial breast irradiation.In addition to clinical trials,patients receiving partial breast irradiation need to be strictly selected and carried out in an orderly manner in experienced medical centers.Current indications for APBI include:1) age ≥50 years;2) invasive tumor ≤3 cm (T1,small T2) with negative margins ≥2 mm;3) low to intermediate grade DCIS,tumor size ≤2.5 cm,negative margins ≥3 mm;4) pN0 breast cancer patients;5)unicentric tumor;6) no lymphovascular invasion;7) no extensive intraductal carcinoma component;8) no neoadjuvant chemotherapy;and 9) preferably ER-positive tumors and invasive lobular carcinoma excluded (not mandatory).

Partial breast irradiation can be performed by intraoperative radiotherapy,brachytherapy or external irradiation.The area of irradiation is the breast tumor bed.Recommended irradiation doses include:intraoperative radiotherapy:20 Gy,completed in a single session;brachytherapy:32 Gy/4 Gy/8 f or 30.1 Gy/4.3 Gy/7 f,twice daily,at least 6 h apart,for a total treatment time of 4?5 d;external irradiation:38.5 Gy/10 f,bid,completed in 5 d.Follow-up results of the RAPID study suggested that this segmentation modality has a late cosmetic result that is relatively poor.Currently in China,38.5 Gy/10 f qd,or 40 Gy/10 f qd can also be used.

5.3.2 Radiation therapy after modified radical mastectomy

(1) Indications

Adjuvant radiotherapy should be considered for patients who meet any of the following conditions after modified radical mastectomy:1) Primary tumor larger than 5 cm;or tumor with direct extension to the chest wall and/or the skin;2) More than 3 positive axillary lymph nodes;or metastases in ipsilateral supraclavicualr lymph nodes or internal mammary lymph nodes;and 3) For pT1?2N1 breast cancer patients,radiation therapy is recommended after modified radical mastectomy.However,in patients with no high-risk factors (younger than 50 years,grade III,lymphovascular invasion and HR negative),the omission of adjuvant radiotherapy may be considered;and 4)Indications for radiation therapy after neoadjuvant chemotherapy refer toSection 5.3.3.

(2) Radiation field

1) For patients who underwent modified radical mastectomy,both the chest wall and paraclavicular field should be included.

2) For tumors located in the inner quadrant with 1?3 metastatic lymph nodes,or tumors with more than 4 metastatic lymph nodes,the internal mammary nodes radiation may be considered.

3) After a standard ALND,the axilla is not included in the radiation fields.However,in cases of positive SLNs but no ALND or inadequate ALND,the axilla should be included in the radiation fields.

(3) Radiation techniques

Radiation therapy after modified radical surgery can be performed by 2D irradiation,3D conformal radiotherapy,fixed-field or rotational intensity modulation irradiation techniques.Regardless of the technique used,CT localization and outlining of the target area and organs at risk are recommended,and CT images are imported onto the 3D planned treatment system for individualized planning assessment to accurately assess the dose distribution to the target area and organs at risk.Also,regardless of the irradiation technique used,care should be taken to add tissue compensators (40%?60% of the irradiation dose) to the chest wall surface to ensure adequate skin dose.

The irradiation field can be designed with reference to the traditional 2D irradiation mode,for example,the supraclavicular area can be irradiated with a single anterior field or anterior-posterior paired fields,and the internal breast lymphatic drainage area can be irradiated with electron,it is required that 90% of the target volume in the supraclavicular and internal breast lymphatic drainage area should be irradiated with 90% of the dose.Chest wall can be irradiated by tangential field or electron,and when electron is used,the irradiation range can be referred to the traditional 2D field distribution method,the full surgical scar and free flap range should be included.

Compared with 2D radiotherapy,3D conformal and intensity modulated radiotherapy help to ensure that the prescribed dose is achieved in the target area,improves dose uniformity within the target area,reduces the irradiated dose to normal tissues,better handles the interface between the chest wall and regional lymph node irradiation fields,and individualizes the treatment of patients,but at the cost of increasing the complexity of plan designing.Individualized selection of irradiation technique is recommended.When using conformal intensity modulated radiotherapy,the target area should be accurately outlined to ensure cardiopulmonary safety and low irradiation dose to normal organs,such as the thyroid,the healthy breast,and the affected shoulder joint.

(4) Radiation dose and segmentation pattern

The recommended radiation dose after modified radical surgery is 50 Gy/2 Gy/25 f.In experienced units,large fractionated radiotherapy may be considered:40.0?43.5 Gy/15 f/3 w.

(5) Arrangement of radiotherapy and systemic therapy

For patients with planned adjuvant chemotherapy,radiotherapy should be performed after chemotherapy.And for patients without adjuvant chemotherapy,radiotherapy should be performed within 8 weeks after surgery on the premise of good wound healing.Herceptin can be given concurrently with radiotherapy.Before the initiation of radiotherapy,make sure that the left ventricular ejection fraction (LVEF) is over 50%.Radiation dose to the heart should be as low as possible,especially for patients with tumor on the left breast.Endocrine therapy can be given concurrently with radiotherapy.

5.3.3 Radiotherapy under special circumstances

(1) Radiation therapy after neoadjuvant chemotherapy

1) Radiation therapy after neoadjuvant chemotherapy followed by BCS:For patients underwent neoadjuvant chemotherapy and BCS,postoperative whole-breast +tumor bed radiation should be performed regardless of the response to treatment.The target area of the tumor bed is generally determined by the actual extent of BCS after neoadjuvant chemotherapy,and if necessary,by the prechemotherapy clinical and postoperative pathologic staging(the key is the accurate assessment of the modality of primary tumor regression before surgery,as well as the negative margins).Postoperative irradiation of the whole breast combined with nodal regional irradiation is routinely performed in all patients with positive postoperative pathological lymph nodes or in patients with stage III initial clinical staging prior to neoadjuvant chemotherapy.In principle,postoperative whole-breast and regional nodal irradiation is still mandatory for ypN0 patients after neoadjuvant chemotherapy;in clinical practice,nodal regional irradiation can be carefully avoided for selected low-risk patients who have reached pathological complete response (pCR) after neoadjuvant chemotherapy,＞40 years of age,and no other risk factors (e.g.,histologic grade 3,vascular thrombosis,hormone receptor negativity,etc.).

The dose of prophylactic radiotherapy after BCS after neoadjuvant chemotherapy was as described above for the absence of neoadjuvant chemotherapy (Section 5.3.1).

2) Radiotherapy after modified radical surgery following neoadjuvant chemotherapy:No data regarding adjuvant radiotherapy after neoadjuvant chemotherapy are currently available.The current recommendation is to incorportate clinical stage before neoadjuvant therapy and pathological stage after neoadjuvant chemotherapy with the patient and tumor characteristics.The indications for radiotherapy are as follows:a) Patients with initial stage III tumor before neoadjuvant chemotherapy and positive axillary lymph nodes after neoadjuvant chemotherapy;and b) Patients with initial clinical stage II (cN1) tumors and negative axillary lymph nodes after neoadjuvant chemotherapy are encouraged to participate in clinical trials as postoperative radiotherapy is controversial.Patients with high-risk factors can be selected for postoperative radiotherapy:age ≤40 years,ypT ＞2 cm,lymphovascular invasion,molecular subtypes with poor prognosis (hormone receptor negative,HER2 positive),etc.

The dose and fractionation pattern of radiation therapy for patients underwent modified radical surgery after neoadjuvant chemotherapy are essentially the same as for patients without neoadjuvant chemotherapy.For patients with skin invasion or a diagnosis of inflammatory breast cancer,after irradiating the whole chest wall 50 Gy/25 f,an additional 10?16 Gy to the chest wall in the free flap area may be considered.The number of skin fillers can be increased during radiotherapy to ensure adequate skin dose.For patients with supraclavicular or internal mammary lymph node metastases at the time of initial diagnosis,additional dose should be given.If complete response of supraclavicular or internal mammary lymph nodes is achieved after chemotherapy,the dose should be increased by 10 Gy in 5 doses;if residual supraclavicular or internal mammary lymph nodes remain after chemotherapy,the dose should be increased by 16?20 Gy in 8?10 fractions.Patients were required to have CT examination during baseline evaluation,and lymph node metastasis should be confirmed by biopsy.

(2) Radiation therapy after breast reconstruction surgery

The indications for radiotherapy in patients underwent breast reconstruction after total mastectomy are the same as those for patients without reconstruction,but the risk of radiotherapy-related complications with reconstructive implants and the technical challenges of reconstruction need to be weighed.Autologous reconstructed tissue tolerates radiotherapy well,and radiotherapy generally does not increase the risk of complications in patients with autologous reconstruction.Since the autologous flap tissue may shrink after radiotherapy,it is possible to design the reconstructed breast volume slightly larger than the contralateral breast at the time of surgery.The use of implant reconstruction is increasing,and radiation therapy increases the risk of contracture of the prosthetic envelope and impairs the cosmetic outcome.In two-staged reconstruction,the timing of radiation therapy can be either before or after permanent prosthesis implantation.Radiotherapy prior to permanent prosthesis implantation,with direct irradiation of the tissue expander,has a low impact on subsequent prosthetic contracture,but an increased rate of reconstruction failure.Radiotherapy after permanent prosthesis implantation has a low reconstruction failure rate,but an increased complication of prosthetic contracture.In addition,the timing of the initiation of radiotherapy needs to take into account the effect of delayed radiotherapy due to the implantation of permanent prosthesis on the tumor outcome,and it is best not to delay radiotherapy for too long in patients at high risk of recurrence.For patients treated with radiotherapy prior to permanent prosthesis implantation,to improve the success rate of reconstruction,a dilator injection procedure is completed prior to radiotherapy positioning to ensure adequate tissue expansion,and saline is not allowed to be injected or withdrawn from the dilator until the end of radiotherapy to ensure consistent volume and position of the target area.The radiation therapy required irradiation of the ipsilateral chest wall+regional lymphatic drainage area,and the principle of irradiation of the lymphatic drainage area was the same as in patients without reconstruction.The dose of radiation therapy is divided into conventional fractions of 50 Gy in 25 fractions over 5 weeks.After conventional radical mastectomy,5%?10% of the gland still remains,the rich network of lymphatic ducts in the subcutaneous tissue is an important route for tumor metastasis to the axillary fossa or internal breast lymph nodes,which are important targets for radiotherapy to the chest wall after reconstruction.Because of the superficial location and part of the target area is located in the dose build-up area,special attention is paid to the design of the radiotherapy plan to cover the whole target area in case of positional error.Depending on the extent of the built-up area of the radiotherapy technique used,it is recommended that the chest wall skin surface with tissue padding should be irradiated 10?15 times to ensure adequate doses to the target area.

(3) Radiotherapy after loco-regional recurrence

Most loco-regional recurrence are found in the chest wall and supraclavicular regions.Generally,patients with unifocal chest wall recurrence should undergo extensive local tumor excision and subsequent radiotherapy.If the tumor is unresectable,radiotherapy is given first.For patients without previous radiotherapy,the chest wall and paraclavicular field should be irradiated.If there is no sign of recurrence in the axilla or internal mammary nodes,prophylactic irradiation is unnecessary.

The treatment for loco-regional recurrence must be based on cytological or histological confirmation.

5.4 Chemotherapy

5.4.1 Adjuvant chemotherapy

After a comprehensive analysis of the patient’s health conditions (age,menstrual status,blood test results,vital organs’ function,comorbidities,etc.),tumor characteristics(histological type,tumor grade,lymph node status,HER2 and hormone receptor status,lymphovascular invation) and potential treatment strategies (chemotherapy,endocrine therapy,anti-HER2 therapy,etc.),if the potential benefit of chemotherapy outweighs the risk,adjuvant chemotherapy may be given.

(1) Indications

1) Patients with positive axillary lymph nodes.

2) For postmenopausal patients with 1?3 positive nodes,and no other risk factors (HR negative,HER2 positive,large tumor,high grade,etc.),or patients who are deemed unfit for chemotherapy,endocrine therapy alone may be considered.

3) For node negative patients,postoperative adjuvant chemotherapy is only suitable for patients with other risk factors (age ＜35 years,tumor diameter ＞2 cm,high-grade tumor,presence of lymphovascular invasion,HER2 positive,ER/PR negative,etc.).

(2) Relative contraindications

1) Pregnancy (chemotherapy is usually contraindicated in the first trimester,and should be carefully selected in the second trimester).

2) Patients with marked exhaustion or cachexia.3) Patients who refuse adjuvant chemotherapy.

4) Patients with severe infection,high fever,water electrolyte and acid-base imbalance.

5) Patients with gastrointestinal obstruction or perforation.

6) Patients with low bone marrow reserve,white blood cells≤3.5×109/L,platelets ≤80×109/L.

7) Patients with cardiovascular,hepatic or renal dysfunction.

(3) Selection of adjuvant chemotherapy regimens

1) Commonly used regimens:a) Anthracycline-based regimen,AC (doxorubicin+cyclophosphamide),EC(Epirubicin+cyclophosphamide);Though with limited data,pirarubicin (THP) is applicable to replace doxorubicin in Chinese clinical practice,the recommended dose is 40?50 mg/m2.b) Concurrent combination of anthracyclines and taxanes,such as TAC (T:docetaxel).c)Sequential anthracycline and taxane regimens,such as sequential AC and paclitaxel (once a week),sequential AC and docetaxel (once every 3 weeks),sequential dose-dense AC and paclitaxel (once every 2 weeks),sequential dosedense AC and paclitaxel (once a week).d) Anthracyclinefree regimen:TC (docetaxel/cyclophosphamide 4 or 6 courses) is suitable for some patients.e) Adjuvant capecitabine (combined or sequential) may be considered in triple-negative breast cancer.

2) HER2-positive breast cancer:For commonly used regimens please refer toSection 5.6.3.

(4) Special considerations

1) The purpose of adjuvant chemotherapy is to seek cure,so emphasis is placed on the standardization of treatment.

2) Attention should be paid to the order of drug administration,as well as infusion time and dose intensity.

3) Chemotherapy regimen selection is based on risk of recurrence,individual tolerability,patients’ will,and existing clinical evidence.Appropriate regimens to prevent and treat nausea/vomit and myelosuppression should be incorporated.

4) For adjuvant chemotherapy,generally 4?8 cycles of chemotherapy are given.Treatment plans in patients over 70 years old need to be individualized.

5) Adjuvant chemotherapy is generally not given simultaneously with endocrine therapy or radiotherapy.Endocrine therapy may start after chemotherapy.Radiotherapy and endocrine therapy may be given sequentially or simultaneously.

6) Chemotherapy should be given according to the recommended dose.If dose reduction is necessary,it is generally recommended that a dose intensity over 85%should be maintained.

7) Ovarian function suppression may be considered in premenopausal patients with hormone receptor negative disease to protect ovarian function during chemotherapy.Ovarian function suppression should start 1?2 weeks before chemotherapy,and the last dose should be given 2 weeks after the end of chemotherapy.

8) Anthracyclines are cardiotoxic and LVEF must be monitored,usually once every 3 months.

9) Informed consents are mandatory.

5.4.2 Neoadjuvant chemotherapy

Neoadjuvant chemotherapy is given before local treatment(surgery or radiotherapy).The purpose of neoadjuvant chemotherapy is to down stage tumors,turn inoperable tumors to operable tumors and increase the rate of BCS.

(1) Indications

1) Stage IIIA (excluding T3N1M0),IIIB and IIIC tumors that need to be adequately down-staged before surgery.

2) To increase the rate of BCS in stage IIA,IIB,IIIA(T3N1M0 only) tumors.

3) Neoadjuvant therapy is feasible for inoperable occult breast cancer (occult breast cancer is defined as axillary lymph node metastasis as the first symptom,and the primary breast cancer cannot be found).

(2) Contraindications

1) Pathological confirmation of breast cancer or immunohistochemical results (ER,PR,HER2 and Ki-67) not acquired.Cytology is not the recommended method of diagnosis.

2) Neoadjuvant chemotherapy is an absolute contraindication for females in early pregnancy,while neoadjuvant chemotherapy should be carefully selected for females in middle and late pregnancy,which is relatively contraindicated and has been successfully applied in foreign cases.

3) Patients with significant impairment of cardiovascular,hepatic or renal functions.

4) The primary tumor shows extensive carcinomain situand no clear presence of invasive cancer.

5) The tumor is clinically inaccessible or unable to evaluate.

6) The patient refuse preoperative neoadjuvant therapy.

7) Patients with severe infection,high fever,water electrolyte and acid-base balance disorder.

8) Patients with insufficient bone marrow reserve,neutrophils ≤1.5×109/L and platelets ≤75×109/L before treatment.

(3) Selection of neoadjuvant chemotherapy regimens

1) For HR-positive/HER2-negative breast cancer patients with down-staging or breast-conserving needs,neoadjuvant chemotherapy should be recommended.

2) For HER2-positive and triple-negative breast cancer patients,the indications for neoadjuvant therapy can be appropriately extended,therapeutic response can be evaluated after neoadjuvant therapy at an early stage,and adjuvant therapy can be adjusted according to postoperative pathological response.

3) For HER2-positive breast cancer patients with neoadjuvant chemotherapy indications,neoadjuvant chemotherapy may be performed with an anthracycline and taxane regimen or an anthracycline-free regimen combined with trastuzumab ± pertuzumab.The addition of pertuzumab can further improve pCR rate,especially in HR negative and lymph node positive patients.

4) Neoadjuvant regimens with both anthracycline and taxane are recommended for patients with triple-negative breast cancer.Platinum can be used as part of a neoadjuvant regimen for triple-negative patients to increase the probability of tumor regression and the possibility of pCR,but the potential benefit and harm should be weighed,as it may not translate into long-term survival benefits.BRCA1/2 pathogenic or suspected pathogenic mutation alone is not sufficient to justify the choice of platinum-containing therapy.Neoadjuvant therapy with taxanes alone plus platinum may be considered for patients with underlying cardiac disease.PD-1/PD-L1 antibody has not yet obtained relevant indications in China,and its longterm toxicity and benefit are unknown.Therefore,adding immune checkpoint inhibitors in neoadjuvant therapy for such patients is not routinely recommended.

(4) Special considerations

1) Before the initiation of chemotherapy,histological diagnosis must be established and immunohistochemical examinations must be performed.Suspicious regional lymph nodes may be assessed by needle aspiration cytology.2) Neoadjuvant chemotherapy is not routinely recommended for stage I breast cancer.

3) In patients with partial response to or stable to neoadjuvant therapy,it is recommended all of the prescribed number of cycles before surgery should be finished.

4) Responses of the primary tumor and axillary lymph nodes should be evaluated by means of physical examination and imaging tests according to the Response Evaluation Criteria in Solid Tumors (RECIST) or WHO criteria.

5) Switching to surgery,radiation therapy or other systemic treatments (non-cross-resistent chemotherapy regimens or neoadjuvant endocrine therapy) should be considered when tumor shows no response.

6) After neoadjuvant chemotherapy,even if the tumor is no longer clinically detectable,definitive surgery must be performed.

7) The selection of adjuvant chemotherapy regimen should be based on the neoadjuvant regimen cycles,therapeutic response and postoperative pathological results.

8) It is recommended that adjuvant radiotherapy and the range of radiotherapy should be determined according to the clinical stage of the tumor before chemotherapy.

(5) Adjuvant systemic treatment

For patients who did not have pCR after neoadjuvant chemotherapy (a full course of neoadjuvant chemotherapy),especially for patients with triple-negative breast cancer,the additional 6?8 courses of capecitabine can be considered after surgery.For HER2-positive cancers,adjuvant trastuzumab emtansine (T-DM1) is preferred,or trastuzumab combined with pertuzumab can be continued for a total of 1 year.Studies have shown that extended neratinib treatment for 1 year can further reduce the risk of recurrence in selected populations.For HR-positive patients,endocrine therapy should be given.

5.4.3 Chemotherapy for advanced breast cancer

The main purpose of treatment is not to cure these patients,but to improve the quality of their lives,and prolong survival.Chemotherapy and endocrine therapy are the main treatment methods,surgery or radiotherapy may be considered when necessary.Individualized treatment plans are made according to the characteristics of the primary tumor,previous treatment,disease-free survival,site of metastasis,speed of progression,patient status and other factors.

Baseline assessments include a complete medical history and physical examination,blood tests,chest X-ray or CT,abdominal ultrasound,bone scan,etc.Radiology confirmation for patients with localized bone pain or suspicious bone scan results is required before a diagnosis of bone metastasis can be established.Abdominal CT or MRI,head CT or MRI may be necessary for some patients.PET-CT is optional but is not routinely recommended for patient evaluation.Biopsy of the metastasis or recurrence site is recommended when possible,together with assessments of molecular markers such as ER,PR,HER2 and Ki-67.

(1) Patients who meet one of the following conditions may consider chemotherapy:

1) ER/PR negative or low expression.

2) Extensive or symptomatic visceral metastases.

3) ER/PR positive but endocrine therapy non-responsive.

(2) Chemotherapy regimens

Commonly used chemotherapy drugs to treat late-stage breast cancer include anthracyclines,taxanes,vinorelbine,capecitabine,gemcitabine,platinum,etc.Individualized treatment plan should be developed based on the extent and the molecular characteristics of the tumor,previous treatment and patient’s will.Single-agent chemotherapy or polychemotherapy should be carefully chosen and offered to patients at different stages.

1) Single-agent chemotherapy Single-agent chemotherapy is preferred for patients with low tumor burden and no sign of rapid progression.Singleagent chemotherapy is also preferred for old or frail patients with tolerability issues.

Failure after anthracycline (taxane) is commonly defined as disease progression during rescue chemotherapy with anthracycline (taxane) or recurrence and metastasis within 12 months of the end of adjuvant therapy.For patients who have failed previous anthracycline therapy,single-drug or combination taxane regimens such as paclitaxel,docetaxel and albumin-bound paclitaxel are usually preferred.There is currently no standard chemotherapy regimen for patients who have failed both anthracycline and taxane therapies,and other single-agent or combination regimens may be considered.

Common monotherapies include anthracycline such as doxorubicin,epirubicin,pirubicin and polyethylene glycol liposome doxorubicin;taxanes,such as paclitaxel,docetaxel,albumin binding paclitaxel;anti-metabolites such as capecitabine,gemcitabine,etc.Non-taxane microtubule formation inhibitors,such as vinorelbine,alibrine,utedrone,etc.Etoposide capsules,cyclophosphamide tablets and other oral convenient,can be used as late-line treatment.

2) Polychemotherapy

Polyche motherapy is suitable for patients with rapid disease progression,large tumor load or obvious symptoms.The selection of polyche motherapy regimen is diverse,which is mainly based on interaction between drugs,toxicity of the drugs,and individual patient status.The combination of three or more chemotherapy drugs is not recommended.a)For triple-negative breast cancer,GP regimen (gemcitabine combined with cisplatin),GC regimen (gemcitabine combined with carboplatin),AP regimen (albuminpaclitaxel combined with cisplatin/carboplatin) and PC regimen (other taxane-based drugs combined with carboplatin/cisplatin) can be selected.b) Chemotherapy can be combined with proper targeted therapy.c) It is necessary to assess efficacy,adverse effects and patient quality of life after 4?8 courses.d) There is no standard treatment for patients with multiple chemotherapy failures,and patients are encouraged to participate in clinical trials.Sacituzumab govitecan is an important targeted treatment option for triple-negative breast cancer,which has been approved by the Food and Drug Administration (FDA) in the United States,but is still being studied in China.f) For HER2-positive cancers,chemotherapy should be combined with HER2-targeted drugs.

3) Maintenance chemotherapy

For patients who have completed 4?6 cycles of chemotherapy,if the treatment is effective and well tolerated,the treatment can continue until the progression of the disease or the occurrence of intolerable toxicity.Maintenance chemotherapy may be considered for those whose tumors showed response but have tolerability issues or have no desire to continue combination chemotherapy.Maintenance chemotherapy of a single agent in the original combination regimen may be selected.Endocrine plus or minus targeted therapy may also be considered for hormone receptor positive patients.Patient management should be strengthened in maintenance therapy,and efficacy and adverse effects should be evaluated regularly.

5.5 Endocrine therapy

5.5.1 Adjuvant endocrine therapy

(1) Indications

1) Patients with hormone receptor ER and/or PR positive invasive breast cancer should receive adjuvant endocrine therapy.According to the latest American Society of Clinical Oncology/College of American Pathology(ASCO/CAP) guidelines,tumors with 1%?100% ER immunohistochemical staining are considered ER-positive,but 1%?10% of ER immunohistochemical staining indicates low ER expression.The biological behavior of ER low expression tumors is usually similar to that of ERnegative breast cancer,and there is limited benefit regarding adjuvant endocrinology,which should also be taken into account when making treatment decisions.

2) Five years of endocrine therapy is considered for patients with carcinomain situif a) patients underwent BCS and radiotherapy,especially patients with hormone-receptor positive DCIS;b) DCIS patients underwent only local resection;and c) patients underwent contralateral prophylactic mastectomy.

(2) Contraindications

1) Contraindications to endocrine drugs:a history of deep venous thrombosis or pulmonary embolism.

2) Patients with severe liver or kidney dysfunction.

3) Pregnant females and patients with allergy to endocrine drugs.

(3) Drug selection

1) Tamoxifen is the first choice in adjuvant endocrine therapy for premenopausal patients.

2) In premenopausal patients with high recurrence risk,ovarian suppression is recommended.Ovarian suppression plus aromatase inhibitor is recommended for young (＜35 years of age) breast cancer patients.Tamoxifen or aromatase inhibitors plus ovariectomy or ovarian suppression for 5 years may be considered.

3) Sequential tamoxifen and aromatase inhibitor treatment may be considered if the patient is menopausal.

4) The third-generation aromatase inhibitors are preferred for postmenopausal patients,and upfront use is recommended.

5) Postmenopausal patients who cannot tolerate aromatase inhibitors can still choose tamoxifen.

(4) Special considerations

1) Estradiol and follicle-stimulating hormone levels should be measured before chemotherapy to determine menstrual status.

2) The duration of adjuvant endocrine therapy is usually 5 years,the extension of endocrine therapy needs to be individualized,and a comprehensive decision should be made based on the risk factors and the will of patients.For high-risk premenopausal patients,if the patient remains premenopausal after 5 years of tamoxifen,tamoxifen to 10 years may be considered.If the patient becomes postmenopausal during tamoxifen treatment,aromatase inhibitor for another 5 years after 5 years of tamoxifen may be considered.

3) Adjuvant endocrine therapy (except luteinizing hormone releasing hormone agonists) is not recommended to be used together with adjuvant chemotherapy.It is generally used after chemotherapy and can be used concurrently with radiotherapy and trastuzumab.

4) Adjuvant endocrine therapy is not recommended for patients with negative ER and PR.

5) Monitoring and management of common adverse effects in endocrine therapy:a) Contraception is needed during tamoxifen,ultrasound monitoring of endometrium should be carried out,and gynecological examination should be conducted every 6?12 months.b) For patients on aromatase inhibitors,bone mineral density should be monitored and calcium and vitamin D should be supplemented.Patients with severe osteoporosis can be treated with regular anti-osteoporosis therapy.c) Blood lipids should be monitored during treatment with aromatase inhibitors,and corresponding treatment should be given to patients with dyslipidemia when necessary.Discontinuation or change of regimen should be considered for severe adverse reactions during endocrine therapy.

5.5.2 Endocrine therapy for advanced breast cancer

(1) Indications for first-line endocrine therapy:1)Patients older than 35 years;2) disease-free survival more than 2 years (this limit needs to be reconsidered when combined with targeted therapy);3) bone and soft tissue metastases only;4) asymptomatic visceral metastasis;5) ER and/or PR positive;and 6) patients with unknown receptors or negative receptors,if disease progression is slow,may be offered a chance of endocrine therapy at certain stage of disease.

(2) Drug selection

1) Endocrine drugs for postmenopausal patients:aromatase inhibitors include non-steroidal (anastrozole and letrozole),steroids (exemestane),ER modifiers (tamoxifen and torimefene),ER modifiers (fluvestrone),progesterone drugs (megesterone),androgens (flumetestosterone),and high-dose estrogens (acetynoestradiol).

2) Endocrine therapy for premenopausal patients:On the basis of ovarian function suppression (luteinizing hormone releasing hormone agonists or ovariectomy),the management of postmenopausal patients can be applied to premenopausal patients.In the absence of ovarian function suppression,ER modifiers (tamoxifen and toremifene),progesterone drugs (megesterone),androgens(flumetotestosterone),and high-dose estrogen(ethinylestradiol) may be considered.

3) Targeted therapy (CDK4/6 inhibitors,HDAC inhibitors,etc.) together with endocrine therapy may be considered for both premenopausal and postmenopausal patients.

(3) Selection of first-line endocrine therapy for advanced breast cancer

1) Aromatase inhibitors combined with CDK4/6 inhibitors are preferred for first-line endocrine therapy in postmenopausal patients with advanced HR-positive/HER2-negative breast cancer.

2) Endocrine monotherapy may be considered if CDK4/6 inhibitors are not available.For postmenopausal patients,fluvestrone,aromatase inhibitor (AI),ER modulators(tamoxifen and toremifene) can be used;ovarian function suppression (OFS) combined with flurvestrone,OFS combined with AI,OFS combined with ER regulator,and ER regulator alone can be used in premenopausal patients.3) Premenopausal patients with ovarian function suppression can be treated according to postmenopausal patients.

(4) Selection of second-line endocrine therapy for advanced breast cancer

After the failure of first-line endocrine therapy,patients with non-visceral crisis can still choose second-line endocrine therapy plus or minus targeted therapy.Re-use of adjuvant or first-line endocrine agents is not recommended.

1) For patients who have not been treated with CDK4/6 inhibitors:a) Fluvestrant combined with CDK4/6 inhibitors is the preferred choice for second-line endocrine therapy in postmenopausal patients with advanced HRpositive/HER2-negative breast cancer.b) Steroids/nonsteroidal aromatase inhibitors (±OFS) or tamoxifen (±OFS)combined with CDK4/6 inhibitors can also be used.There is currently insufficient evidence to support the continuation of CDK4/6 inhibitors in patients whose tumors progressed during previous treatment including a CDK4/6 inhibitor.

2) If CDK4/6 inhibitors are not available,endocrine monotherapy is also feasible.Fluvestrant,AI and ER modulators (tamoxifen and toremifene) may be used in postmenopausal patients.For premenopausal patients,OFS combined with flulvestrone,OFS combined with AI,OFS combined with ER modifier,and ER modifier alone can be used.

(5) Special considerations

1) Tumor progression after two consecutive lines of endocrine therapy usually indicates drug resistance to endocrine therapy,so cytotoxic drugs should be used.

2) During endocrine therapy,the efficacy should be evaluated every 2?3 months.Tumors with response or stable disease should continue endocrine maintenance therapy.If the tumor progresses,endocrine drugs of other mechanisms or other treatments such as chemotherapy should be considered.

5.6 Targeted therapy

Currently,targeted therapy for HER2-positive breast cancer in China includes trastuzumab,pertuzumab,pyrotinib,T-DM1,lapatinib,etc.

5.6.1 Definition of HER2 positivity

(1)HER2gene amplification:immunohistochemical staining 3+,fluorescentin situhybridization (FISH)positive or colorin situhybridization (CISH) positive.

(2) For patients with HER2 immunohistochemical staining(2+),FISH or CISH should be performed to detectHER2gene amplification.

5.6.2 Precautions

(1) HER2 status must be determined before treatment.

(2) Trastuzumab monoclonal antibody 6 mg/kg (loading dose 8 mg/kg) every 3 weeks,or 2 mg/kg (loading dose 4 mg/kg) weekly are both acceptable.

(3) Patient should be observed for 4?8 h after the first treatment for adverse effects.

(4) Generally,anti-HER2 drugs are not used concurrently with an anthracycline.

(5) Anti-HER2 drugs can be used concurrently with nonanthracycline chemotherapy,endocrine therapy and radiotherapy.

(6) LVEF should be evaluated before trastuzumab treatment and monitored once every 3 months during its use.If LVEF lower than 45% or a decrease of more than 16% occurs,treatment should be suspended,and the dynamic changes of LVEF should be monitored until LVEF recovered to above 45%.Trastuzumab treatment should be discontinued if LEVF does not recover,or if symptoms of heart failure continue.

5.6.3 Postoperative adjuvant targeted therapy

(1) Indications

1) Trastuzumab is recommended for HER2-positive breast cancer patients with primary invasive tumor ＞1 cm (T1c or above).

2) Trastuzumab may be recommended for HER2-positive lymph node negative breast cancer with primary invasive tumor of 0.6?1 cm (T1bN0) and for patients with axillary lymph nodes micrometastases (pN1mi).

3) Trastuzumab is generally not recommended for patients with HER2-positive lymph node negative breast cancer with primary invasive tumor ＜0.5 cm (T1a),but may be considered for patients with other risk factors,such as negative hormone receptor,high grade and high Ki-67.

(2) Relative contraindications

1) LVEF＜40% before treatment.

2) Patient refusal.

(3) Treatment options

1) TCH (P),AC-TH (P) are commonly used regimens.TCH,TC4H (C:Cyclophosphamide) and wPH can be selected for patients with cardiac safety considerations.For patients at high risk of recurrence (such as lymph node positive),dual targeted therapy (trastuzumab and pertuzumab) combined with adjuvant chemotherapy is recommended.Pertuzumab is administered once every 3 weeks at a dose of 420 mg (loading dose 840 mg) for 1 year.For ER+cancers,neratinib for 1 year after completion of trastuzumab therapy may also be considered.

2) For patients with small tumors (tumor diameter ≤1 cm),weekly paclitaxel plus trastuzumab (wPH) is applicable.

(4) Special considerations

1) Concurrent use of anthracyclines and anti-HER2 drugs is not routinely recommended.Anti-HER2 drugs may be used concomitantly with non-anthracycline chemotherapy,endocrine therapy or radiotherapy.

2) Duration of trastuzumab adjuvant therapy is 1 year.

5.6.4 Preoperative neoadjuvant targeted therapy

HER2-positive breast cancer is highly sensitive to HER2-targeted therapy,and anti-HER2 therapy should be included in the neoadjuvant therapy regimen for these patients.

(1) Principles of neoadjuvant targeted therapy

1) Dual targeted therapy (trastuzumab and pertuzumab) is preferred.

2) For HER2-positive breast cancer patients with neoadjuvant indications,neoadjuvant therapy should be performed using anthracycline and taxane containing regimens or anthracycline-free regimens combined with trastuzumab ± pertuzumab.

3) The addition of pertuzumab can further improve the pathological complete response rate,and is recommended for HR-negative and lymph node positive patients.

4) Anthracycline-free regimens such as TCH (P) can be used in patients with anthracycline contraindications,advanced age,or other tolerability issues.

(2) Special considerations

1) Efficacy should be closely monitored during neoadjuvant therapy according to RECIST or WHO standards.Patients whose tumors progressed during neoadjuvant treatment can continue trastuzumab in subsequent neoadjuvant therapy.

2) Patients should complete 1-year trastuzumab +pertuzumab.

3) For HER2-positive patients who did not have pCR after neoadjuvant chemotherapy,adjuvant T-DM1 is preferred,or trastuzumab+pertuzumab should be continued for a total of 1 year.Extended neratinib treatment for 1 year can further reduce the risk of recurrence in selected populations.

4) There is insufficient evidence for neoadjuvant anti-HER2 therapy alone or in combination with endocrine therapy,and its application should be limited to clinical studies.

5.6.5 Targeted treatment for advanced HER2-positive breast cancer

Anti-HER2 therapy is important for advanced HER2-positive breast cancer.

(1) First-line treatment options for advanced HER2-positive tumors

1) Dual targeted therapy (trastuzumab and pertuzumab)combined with taxane-based chmotherapy is usually recommended.Other options include trastuzumab single agent combined with a taxane,and trastuzumab can also be combined with vinorelbine,capecitabine or other chemotherapeutic agents.

2) For patients without using previous trastuzumab or trastuzumab may be re-used (recurrence or metastasis more than 1 year after adjuvant trastuzumab),and treatment is based on trastuzumab ± pertuzumab.The second-line anti-HER2 regimen is recommended for patients with an interval from trastuzumab withdrawal to relapse ≤6?12 months.

3) For HER2-positive/HR-positive patients,if chemotherapy is not suitable or the disease progresses slowly,anti-HER2 therapy combined with endocrine drugs can be considered as first-line treatment options.

(2) Treatment options for disease progression after trastuzumab ± pertuzumab treatment

1) Anti-HER2 therapy should be continued after trastuzumab treatment failure.

2) When the disease progresses after first-line treatment,the following treatment strategies can be selected:a) For patients with trastuzumab ± pertuzumab treatment failure,single drug T-DM1 can prolong the progression-free survival and overall survival;b) pyrotinib combined with capecitabine can prolong progression-free survival compared with lapatinib combined with capecitabine;c)other anti-HER2 drugs:Inetetamab combined with vinorelbine and other chemotherapy regimens can also be used as one of the anti-HER2 treatment options for patients without trastuzumab resistance.Combinations of two targeted agents alone (e.g.Lapatinib+trastuzumab)have also been shown to improve overall survival;d)trastuzumab may be combined with different chemotherapy regimens in multiple lines of treatment;and e) in case of multiple anti-HER2 therapy failures,patients are recommended to participate in clinical trials.

(3) Special considerations

1) Trastuzumab and pertuzumab:Baseline assessment of cardiac function should be performed before treatment and anti-HER2 therapy should be avoided in patients with cardiovascular tolerability issues.

2) Concomitant use of anthracyclines with anti-HER2 therapy should be avoided.

3) Cardiac function should be evaluated regularly during treatment.If LVEF decreases by more than 15% from baseline or is lower than the normal range,anti-HER2 therapy should be suspended,and LVEF should be reevaluated within 3?4 weeks to determine whether anti-HER2 therapy can be continued.

4) T-DM1:Standardized platelet count monitoring should be performed at baseline and during treatment.In case of thrombocytopenia,dose reduction or treatment cessation should be considered.When grade 2 or higher thrombocytopenia occurs,the possibility of persistent thrombocytopenia should be considered.

5) Pyrotinib:Patients should be informed the incidence of diarrhea and other adverse effects and management programs before medication,and diarrhea should be closely monitored.

6.Diagnosis and treatment flowchart

Flowcharts of diagnosis and treatment for breast cancer are shown inFigure 1,2.

Figure 1 Diagnosis procedure for breast cancer.BI-RADS,Breast Imaging Reporting and Data System.

Figure 2 Treatment procedure for breast cancer.

7.Follow-up

(1) Physical examination:Once every 4?6 months in the first 2 years,and then once every 6 months during year 2 to year 5,and once a year after 5 years.

(2) Breast ultrasound:Every 6 months.

(3) Mammography:Once a year.

(4) Chest X-ray or chest CT:Once a year.

(5) Abdominal ultrasound:Once every 6 months during the first 3 years,and then once a year after 3 years.

(6) Bone scan should be performed once a year during the first 5 years,and then once every 2 years after 5 years.

(7) Blood routine tests,blood biochemistry tests and breast cancer markers should be performed once every 6 months.

(8) Pelvic imaging should be performed once a year in patients receiving tamoxifen.

Working group members

Group leader:Binghe Xu

Associate group leaders:Fei Ma,Xiang Wang

Group members:Tao Yu,Yongsheng Wang,Shusen Wang,Yong Wang,Shulian Wang,Jing Wang,Li Fu,Qiang Sun,Guohui Li,Jing Li,Jiong Wu,Jianming Ying,Qingyuan Zhang,Jin Zhang,Jiayi Chen,Feng Jin,Xichun Hu,Wenqiang Wei

Secretary:Qiao Li

Translation group members

Group leader

Xinguang WangKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Group members (listed alphabetically by last name)

Xue ChenKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Dongfeng NiuKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Yang YangKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute

Jingyi ZhaoKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Peking University Cancer Hospital &Institute