Breast cancer: clinical guidelines

List of Abbreviations

ALT – alanine aminotransferase

AST – aspartate aminotransferase

SLNB – sentinel lymph node biopsy

IV – intravenous

i.m. – intramuscularly

ULN – upper limit of normal

CSFs – colony-stimulating factors

GnRH – gonadotropin-releasing hormone

HT – hormone therapy

IHC – immunohistochemical (examination)

CT – computed tomography

RT – radiotherapy

PT – physical therapy

IU – international units

MRI – magnetic resonance imaging

s.c. – subcutaneous

PCR – polymerase chain reaction

PET – positron emission tomography

BC – breast cancer

MRM – radical mastectomy

SFD – single focal dose

PR – progesterone receptors

ER – estrogen receptors

SLN(s) – sentinel lymph node(s)

TFD – total focal dose

CDU – color duplex ultrasonography

US – ultrasound examination

FSH – follicle-stimulating hormone

CT – chemotherapy

ALP – alkaline phosphatase

ECG – electrocardiography

EchoCG – echocardiography

BRCA – breast cancer gene

CDK – cyclin-dependent kinases

HER2 – human epidermal growth factor receptor 2

Ki67 – antigen expressed in dividing cells

NGS – next-generation sequencing

PI3K – phosphatidylinositol 3-kinase

PIK3CA – gene encoding PI3K

Terms and Definitions

ECOG (Eastern Cooperative Oncology Group) – a 5-grade scale for assessing the general condition of a cancer patient before, during, and after treatment (recommended by the Eastern Cooperative Oncology Group).

Biological therapy – therapy including targeted therapy and immunotherapy that exerts a cytotoxic effect on tumor cells and components of the antitumor system, as well as blocking various stages of oncogenesis.

Sentinel lymph node biopsy (SLNB) – a method of obtaining histological material from a lymph node (nodes) considered to be the first in the path of lymphogenous tumor spread. It is recommended to remove at least 2 lymph nodes. The presence or absence of metastases determines the indications for complete lymphadenectomy.

Boost – additional irradiation of the tumor or the tumor bed after resection.

Reconstructive operations – surgeries aimed at the complete restoration or replacement of a non-functioning organ with an identical organ, as well as restoring the physiological function disrupted during the surgical intervention.

Chemotherapy line – the order of administration of chemotherapeutic agents applied depending on their relation to existing standard protocols.

Chemotherapy cycle – the administration of a chemotherapeutic agent in a specific dose, regimen, and method of administration, taking into account the interval between administrations.

Chemotherapy course – a combination of chemotherapy cycles; the administration of antitumor drugs according to a specific planned schedule with adherence to various time intervals between drug administrations.

Adjuvant chemotherapy – chemotherapy administered after local tumor treatment to eradicate or long-term suppress micrometastases.

Neoadjuvant chemotherapy – chemotherapy administered prior to local tumor treatment to reduce tumor mass, downstage the disease, decrease the extent of subsequent surgery or radiation, or determine tumor sensitivity to the drug therapy.

Systemic chemotherapy – oral, subcutaneous, intravenous, intramuscular, and rectal administration of drugs designed to achieve a general antitumor effect.

Hormone therapy (endocrine therapy) – treatment of neoplasms with drugs acting on the endocrine system, as well as their synthetic analogues acting on hormone receptors.

Immunohistochemical examination – a method of microscopic tissue examination that provides the most specific identification of target substances and is based on treating sections with labeled specific antibodies against the target substance (antigen).

Radical radiation therapy – a curative dose of ionizing radiation delivered to the area of clinical tumor spread and prophylactic irradiation of areas at risk for subclinical involvement, leading to the complete eradication of the tumor and regional metastases.

Radical surgical treatment – a standard intervention developed for each specific tumor localization, involving the removal of the tumor-bearing organ or part of it en bloc with regional metastatic zones within healthy tissues in the absence of distant metastases.

Morphological examination – determination of the histological or cytological structure of the tumor and its degree of differentiation.

Supportive care – therapy aimed at preventing and alleviating symptoms of the disease or symptoms associated with the toxicity of treatments, maintaining a good quality of life for patients, regardless of the stage of the disease and the need for other types of therapy.

Treatment regimen – drug treatment regimens or protocols, usually combining several antitumor agents.

Targeted (molecularly targeted) therapy – antitumor drugs that directionally act on molecules involved in carcinogenesis and determine the ability of the tumor to progress and metastasize.

Progression – an increase of more than 25% in one or more tumors or the appearance of new lesions.

Operable tumor – a tumor whose localization, anatomical and functional impairments in the affected organ, extent of spread, presence of distant metastases, growth type, and histological structure allow for surgical treatment.

Breast-conserving surgery – a surgery that involves the removal of the tumor nodule with a small amount of surrounding healthy tissue, with the possible subsequent administration of one of the types of adjuvant treatment.

Resectable tumor – a tumor that can be technically removed considering the extent of its spread.

Remission – a period of the disease course characterized by a significant attenuation (partial remission) or disappearance (complete remission) of the symptoms (signs) of the disease.

Local recurrence – the emergence of the same tumor in the same organ or at the site of its surgical excision or radiation therapy.

Regional recurrence – the emergence of the same tumor in the regional lymphatic drainage area following surgical excision or radiation therapy.

Locoregional recurrence – the emergence of the same tumor in the regional lymphatic drainage area and in the same organ or at the site of its surgical excision or radiation therapy.

Disseminated cancer = generalized cancer = metastatic cancer – a tumor with distant metastases.

Locally advanced cancer – extension of the tumor beyond the affected organ, involving surrounding tissues and/or lymph nodes, but without the formation of distant metastases.

Primary tumor (tumour) – the primary focus of a malignant neoplasm, the main characteristics of which are size and local extension.

Regional metastases (nodulus) – tumor metastases via the lymphatic system to regional lymph nodes.

Distant metastases (metastasis) – tumor metastases spreading via the hematogenous route to distant organs and tissues.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Breast cancer (BC) – a malignant tumor originating from the breast tissue epithelium.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

There is no single etiological factor for the development of breast cancer. In 3–10% of patients with breast cancer, the development of the disease is associated with mutations in breast cancer genes (BRCA)1, BRCA2, CHEK, NBS1, TP53. In the remaining patients, breast cancer is sporadic in nature.

Risk factors for this pathology include early menarche, late menopause, nulliparity, history of abortions, smoking, alcohol, diabetes mellitus, obesity or elevated body mass index, and low physical activity [1].

1.3 Epidemiology of the Disease or Condition

Breast cancer is the most common malignant disease in women in Russia. In 2018, 70,682 new cases were registered, accounting for 20.9% of the structure of malignant neoplasm incidence in women. The mean age of affected individuals was 61.5 years. The average annual growth rate of incidence (standardized indicator) was 1.97% over the past 10 years. The cumulative risk of developing breast cancer in 2018 was 5.87% given a life expectancy of 74 years. In recent years, there has been an increase in the number of patients diagnosed at stages I–II. Thus, in 2018 this figure was 71.2%, whereas 10 years ago it was 62.7%. The standardized mortality rate decreased from 2008 to 2018 from 17.05 to 14.02, respectively. The risk of dying from breast cancer for women in 2018 was 1.6%. The proportion of women under follow-up for 5 years or more is 59.8%.

In the mortality structure of the female population, breast cancer also ranks first, accounting for 16.2%.

Male breast cancer accounts for less than 1% of tumors of this localization, making up 0.3% of the incidence structure. The principles of diagnosis and treatment of breast cancer in men do not differ from those in women [2].

1.4 Features of Coding the Disease or Condition

Carcinoma in situ of breast (D05):

D05.0 – Lobular carcinoma in situ.

D05.1 – Intraductal carcinoma in situ.

D05.7 – Other carcinoma in situ of breast.

D05.9 – Carcinoma in situ of breast, unspecified.

Malignant neoplasm of breast (C50):

C50.0 – Nipple and areola.

C50.1 – Central portion of breast.

C50.2 – Upper-inner quadrant of breast.

C50.3 – Lower-inner quadrant of breast.

C50.4 – Upper-outer quadrant of breast.

C50.5 – Lower-outer quadrant of breast.

C50.6 – Axillary tail of breast.

C50.8 – Overlapping lesion of breast.

C50.9 – Breast, unspecified.

1.5 Classification of the disease or condition

1.5.1. International Histological Classification

Currently, the 2019 World Health Organization (WHO) International Histological Classification of Breast Tumors [3] is used, according to which the following are distinguished:

1.5.2. Staging

Breast cancer staging should be performed using the 8th edition of the TNM classification by the Union for International Cancer Control (UICC) [4]. Clinical and pathomorphological stages of breast cancer are distinguished, which may differ significantly. Clinical staging is based on the results of clinical examination, while pathomorphological staging is based on the pathologist's report following surgery.

T – primary tumor;

T_x – primary tumor cannot be assessed;

T₀ – no evidence of primary tumor;

T_is (DCIS) – ductal carcinoma in situ;

T_is (Paget) – Paget's disease of the nipple without underlying tumor (if a tumor is present, it is classified by tumor size);

T_1mic – microinvasion[1] ≤0.1 cm in greatest dimension.

Note:

T_1a – tumor >1 mm, but ≤5 mm in greatest dimension;

T_1b – tumor >5 mm, but ≤10 mm in greatest dimension;

T_1c – tumor >10 mm, but ≤20 mm in greatest dimension;

T₂ – tumor >20 mm, but ≤50 mm in greatest dimension;

T₃ – tumor >50 mm in greatest dimension;

T₄ – tumor of any size with direct extension to the chest wall[2] and/or skin;

T_4a – extension to the chest wall, not including invasion restricted to pectoral muscles only;

T_4b – edema (including peau d'orange) or ulceration of the breast skin, or skin satellite nodules confined to the same breast;

T_4c – criteria in both T_4a and T_4b are met;

T_4d – inflammatory breast cancer[3];

N – regional lymph nodes[4];

N_x – regional lymph nodes cannot be assessed;

N₀ – no regional lymph node metastases;

N₁ – metastases in movable ipsilateral axillary lymph node(s);

N₂ – metastases in ipsilateral axillary lymph nodes matted or fixed to one another, or clinical evidence of metastatic internal mammary (parasternal) lymph nodes in the absence of clinically evident axillary lymph node metastases;

N_2a – metastases in ipsilateral axillary lymph nodes matted or fixed to one another;

N_2b – clinical evidence of metastatic internal mammary (parasternal) lymph nodes in the absence of clinically evident axillary lymph node metastases;

N₃ – metastases in ipsilateral infraclavicular lymph node(s), or clinical evidence of metastatic internal mammary (parasternal) lymph node(s) in the presence of clinically evident axillary lymph node metastases, or metastases in ipsilateral supraclavicular lymph node(s) (regardless of axillary and internal mammary lymph node status);

N_3a – metastases in ipsilateral infraclavicular lymph node(s);

N_3b – metastases in internal mammary (parasternal) lymph nodes with clinical evidence of axillary lymph node metastases;

N_3c – metastases in ipsilateral supraclavicular lymph node(s).

M – distant metastasis;

M₀ – no distant metastasis;

M₁ – distant metastasis present[5].

Pathological classification

pT – primary tumor:

– pathological assessment requires examination of the primary tumor; the resection margins must be free of tumor tissue;

– if there is only microscopic tumor involvement at the resection margin, the case may still be classified as pT;

– measurement of the invasive component is mandatory for pT classification;

pN – regional lymph nodes.

Pathological classification requires axillary lymphadenectomy (Level I). Such an excision specimen typically contains about 6 lymph nodes. One or more sentinel lymph nodes are examined to refine the pathomorphological classification. If classification is based solely on sentinel lymph node biopsy (SLNB) without additional axillary lymph node dissection, it is designated with the suffix (sn), e.g., pN₁(sn);

pNnx – data insufficient (no lymph nodes found or not removed);

pN₀ – no regional lymph node metastasis on histological examination, with no additional methods used to detect isolated tumor cells;

pN₀ (I-) – no regional lymph node metastasis on histological and immunohistochemical (IHC) examination;

pN₀ (I+) – no regional lymph node metastasis on histological examination;

pN₁ – micrometastases or metastases in 1–3 axillary lymph nodes and/or microscopic disease in internal mammary (parasternal) lymph nodes detected by sentinel lymph node biopsy (clinically undetected);

pN_1mic – micrometastases (greater than 0.2 mm, but not more than 2.0 mm);

pN_1a – metastases in 1–3 axillary lymph nodes, with at least one metastasis greater than 2 mm in greatest dimension;

pN_1b – microscopic disease in internal mammary (parasternal) lymph nodes detected by sentinel lymph node biopsy (clinically undetected);

pN_1c – metastases in 1–3 axillary lymph nodes and microscopic disease in internal mammary (parasternal) lymph nodes detected by sentinel lymph node biopsy (clinically undetected);

pN₂ – metastases in 4–9 axillary lymph nodes, or clinical evidence of internal mammary (parasternal) lymph node metastases in the absence of axillary lymph node metastases;

pN_2a – metastases in 4–9 axillary lymph nodes (at least one tumor deposit ≥2 mm);

pN_2b – clinically detected metastasis in internal mammary (parasternal) lymph nodes with absence of axillary lymph node metastases;

pN₃ – metastases in 10 or more axillary lymph nodes, or in subclavicular lymph nodes, or clinically detected metastasis in internal mammary (parasternal) and axillary lymph nodes, or metastases in 4 or more axillary lymph nodes with microscopic disease in clinically negative internal mammary (parasternal) lymph nodes, or supraclavicular lymph node metastases;

pN_3a – metastases in 10 or more axillary lymph nodes (>2 mm) or in subclavicular lymph nodes;

pN_3b – clinically detected metastasis in internal mammary (parasternal) and axillary lymph nodes, or metastases in more than 3 axillary lymph nodes with microscopic disease in clinically negative internal mammary (parasternal) lymph nodes;

pN_3c – ipsilateral supraclavicular lymph node metastases;

pM – distant metastasis;

pM – categories corresponding to the M category;

G – tumor grade;

Gx – grade cannot be assessed;

G₁ – well differentiated, 3–5 points on the SBR scale[6];

G₂ – moderately differentiated, 6–7 points on the SBR scale;

G₃ – poorly differentiated, 8–9 points on the SBR scale;

G₄ – undifferentiated tumor;

ypT – primary tumor status following medical treatment;

ypN – regional lymph node status following medical treatment;

ypN – post-treatment assessment should be performed in the same manner as pre-treatment assessment (clinical N).

The (sn) descriptor is used if the sentinel lymph node was evaluated after treatment. If the (sn) descriptor is absent, it is assumed that the axillary lymph nodes were evaluated after dissection.

The X designation (ypN_X) should be used if post-treatment ypN assessment (sn) or axillary lymph node dissection was not performed.

The N category is identical to that used for pN.

Clinical (anatomic) staging of breast cancer is presented in Table 1.

Table 1. Breast cancer stage grouping

[1]Microinvasion is the extension of cancer cells through the basement membrane into adjacent tissues with a focus measuring no more than 0.1 cm in greatest dimension. In the case of multiple foci, classification is based on the largest focus. The sum of the sizes of individual foci should not be used. The presence of multiple foci must be noted in the same manner as for multiple invasive carcinomas.

[2]The chest wall includes ribs, intercostal muscles, and serratus anterior muscle, but excludes the pectoral muscles.

[3]Inflammatory breast cancer is characterized by diffuse skin thickening with a rigid border, usually without an underlying palpable mass. If skin biopsies are negative and there is no localized primary tumor, the pTx category is used for pathologic classification, and T4d for clinical classification. The pT category is determined by the invasive component. Skin dimpling, nipple retraction, or other skin changes, except those classified under T_4b and T_4d, may be classified as T₁, T₂, and T₃ without affecting the stage.

[4] The descriptors (sn) or (f) should be added to the N category to indicate the method used to confirm metastatic lymph node involvement: sentinel lymph node biopsy (sn) or fine-needle aspiration / core needle biopsy (f) (without subsequent lymph node removal), respectively.

[5] Lung – pul, bone – oss, liver – hep, pleura – ple, peritoneum – per, bone marrow – mar, brain – bra, skin – ski, adrenal glands – adr, lymph nodes – lym, other – oth.

[6] SBR – Scarff-Bloom-Richardson scale, Nottingham modification

1.6 Clinical presentation of the disease or condition

[0]Clinical forms of breast cancer include: nodular, diffuse (edematous-infiltrative, erysipeloid, mastitis-like, and en cuirasse), as well as Paget's disease of the nipple.

The primary clinical manifestation of the nodular form is a distinct mass within the breast tissue, although the clinical presentation is extremely diverse and depends primarily on the stage of the disease. Symptoms of nodular breast cancer can be conventionally divided into those characteristic of early and advanced stages.

Clinical symptoms of early-stage disease include:

• presence of a tumor node in the breast tissue;
• firm tumor consistency (the tumor may be woody or even stony hard);
• limited mobility or complete fixation; usually painless; presence of the "umbilication" sign (skin dimpling over the tumor when the skin is moved);
• presence of a single firm, mobile lymph node in the ipsilateral axilla, or several similar lymph nodes that are not matted together;
• bloody nipple discharge, which occurs exclusively in ductal carcinoma in situ and intraductal papilloma.

Symptoms characteristic of more advanced tumor stages include:

• visible skin deformation over the tumor (especially when examined with arms raised);
• pronounced "umbilication" (dimpling) of the skin over the tumor;
• lymphedema signs – the "peau d'orange" (orange peel) sign over or beyond the tumor;
• tumor invasion of the skin and/or ulceration;
• marked thickening of the nipple and the areolar fold (Krause's sign);
• nipple retraction and fixation;
• breast deformation, reduction or increase in size, elevation, fixation to the chest wall;
• multiple firm, poorly mobile or fixed lymph nodes in the ipsilateral axilla, sometimes forming matted conglomerates;
• firm ipsilateral supraclavicular lymph nodes.

Diffuse forms are characterized by diffuse induration of the entire breast tissue due to tumor infiltration, enlargement, skin erythema and local hyperthermia (mastitis-like and erysipeloid forms may present with a systemic fever response), a pronounced "peau d'orange" sign across the entire breast surface, marked thickening of the nipple and areolar fold, nipple retraction and firm fixation. In the vast majority of cases, regional axillary lymph nodes are involved. In some cases, differential diagnosis from mastitis and erysipelas is necessary. Primary diffuse forms are distinguished, where no distinct tumor mass is palpable, and secondary forms, where a tumor (usually large) is present, and edema and infiltration of the breast and skin are caused by lymphatic obstruction due to massive regional lymph node involvement.

Paget's disease begins with dry or weeping crusts in the nipple area, redness, and nipple thickening. The process may spread to the areola. Gradually, the nipple flattens, ulceration may develop, and the process extends to the skin of the breast beyond the areola. Simultaneously, the process may spread along the major lactiferous ducts deep into the breast, forming a tumor mass within the tissue. Later, regional lymph node metastases appear.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis or condition:

1. anamnestic data;
2. physical examination findings and, in some cases, instrumental tests (recommendations for specific medical interventions are presented in the relevant sections);
3. morphological examination findings.

2.1 Complaints and Anamnesis

Comments: in 3–10% of breast cancer patients, the disease is hereditary and may be associated with mutations in the BRCA1, BRCA2, CHECK, and other genes.

2.2 Physical Examination

Comments: during the examination, attention should be paid to the symmetry of the mammary glands, the condition of the nipple-areola complex, the presence of skin edema and other skin symptoms. Palpation should focus on the presence of node formations and indurations, their mobility, the presence of infiltration in surrounding tissues, as well as the size and consistency of lymph nodes.

2.3 Laboratory Diagnostics

Comments: in hormone-dependent breast cancer in patients younger than 60 years without menstruation, to assess ovarian function and plan hormone therapy (HT), testing is performed for serum follicle-stimulating hormone (FSH) and total blood estradiol levels (for details see section 3.2.4.4).

Comments: when examining biopsy material, the report must indicate the histological variant, grade of differentiation, and the result of determining estrogen receptors (ER)/ progesterone receptors (PR), human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2) (HER2), and the proliferation marker (Ki67).

When examining surgical material, the report must indicate:

• distance to the closest resection margin;
• status of resection margins;
• tumor dimensions in three mutually perpendicular dimensions;
• histological structure of the tumor;
• tumor differentiation grade;
• pT;
• pN (indicating the total number of examined and affected lymph nodes);
• presence of lymphovascular or perineural invasion (negative findings must also be explicitly stated);
• in the presence of prior combined treatment, the degree of pathomorphological tumor response is preferably determined using the RCB scale (a free online calculator is available at http://www.mdanderson.org/education-and-research/resources-for-professionals/clinical-tools- and-resources/clinical-calculators/calculators-cellularity-guide.pdf) (see Appendix G2).

Determination of ER and PR expression levels in the tumor and/or tumor-affected lymph nodes is mandatory; the IHC method is preferred[13]. The result of receptor status determination must include data on the percentage of ER+ and PR+ cells and staining intensity. Simultaneously, IHC methods should be used to determine HER2 and Ki67 expression levels, which are also taken into account when planning treatment. Determination ofHER2 is recommended to be performed only in the invasive component of the tumor. In case of an equivocal IHC resultfor HER2, gene amplification should be determinedHER2/for neu byin in situ hybridization (FISH orCISH) [14].

In patients with metastatic triple-negative breast cancer who have not received treatment for metastatic disease, it is advisable to determine the level of PD-L1 expression on immunocompetent cells (in the primary tumor or, preferably, in a biopsy sample from the metastatic lesion) using the SP142 assay to determine the feasibility of prescribing paclitaxel protein-bound in combination with #atezolizumab** (the dosing regimen is provided in the treatment section) [15].

In patients with advanced hormone-dependent HER2-negative breast cancer, it is advisable to determine PIK3CA gene mutations in a tissue sample of the primary tumor or metastatic lesion to address the issue of prescribing the combination of alpelisib with fulvestrant** (the dosing regimen is provided in the treatment section) [16].

Comments: for indications for puncture, see section 2.5. In cases of suspected Paget's disease, it is recommended to perform a scraping of changes in the nipple and nipple-areola complex followed by cytological examination.

2.4 Instrumental Diagnostics

Comments: indications for breast MRI:

• age under 30 years;
• presence of BRCA1, BRCA2 gene mutations;
• high mammographic breast density;
• presence of breast implants when high-quality mammography is not feasible;
• presence of lobular carcinoma in situ

Comments: Chest CT is the standard staging diagnostic procedure for breast cancer in most developed countries to rule out lung and mediastinal lymph node metastases. In routine practice, this study may be replaced by radiography in patients with minimal local tumor spread.

Comments: in operable breast cancer, whole-body bone scintigraphy is performed if bone pain is present or alkaline phosphatase levels are elevated. In locally advanced and metastatic breast cancer, this study is indicated for all patients.

Comments: The pathomorphological diagnosis is established through the examination of biopsy material, which must be obtained prior to any therapeutic interventions. Core needle biopsy is performed using an automatic or semi-automatic system with a needle diameter of 14-18 G or using a vacuum-assisted system with a needle diameter of 8-12 G. At least three tissue cores must be obtained. The final pathomorphological diagnosis is established in accordance with the current WHO and TNM classifications after examining all resected tissues. When prescribing preoperative systemic therapy, comprehensive clinical staging must be performed prior to the initiation of treatment; core needle biopsy of the tumor is desirable to perform even if surgical treatment is planned as the first-stage intervention.

2.5 Other Procedures

• in women with confirmed breast cancer and a burdened family history (history of breast cancer in close relatives aged ≤50 years, ovarian or fallopian tube cancer, pancreatic cancer, male breast cancer, metastatic prostate cancer);
• in women with confirmed breast cancer diagnosed at age <45 years;
• in women aged < 60 years with triple-negative breast cancer phenotype;
• in primary multiple breast cancer (including, but not limited to, a diagnosed contralateral breast cancer, ovarian or fallopian tube cancer, pancreatic cancer);
• in men with breast cancer [1].

LoR CLoE 5Level of Recommendations – C (Level of Evidence – 5).

Comments: Patients with a personal/family history in whom common hereditary mutations are not detected should be referred for extended testing of germline and/or somatic mutations using next-generation sequencing (NGS).

• echocardiography (EchoCG);
• Holter heart rate monitoring;
• pulmonary function testing;

– duplex scanning of brachiocephalic arteries with color Doppler blood flow mapping;

• ultrasound Dopplerography (USDG) of lower extremity vessels (arteries and veins);
• consultations with a cardiologist, endocrinologist, neurologist, and other specialists as indicated.

GCR CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1. General principles of treatment

It is advisable to formulate the treatment plan at a multidisciplinary team meeting involving a surgeon, oncologist, and radiation therapist. If necessary, it is recommended to involve other specialists (pathologist, anesthesiologist-intensivist, etc.). The recommended algorithm of diagnostic and treatment measures for breast cancer is shown in Fig. 1.

If the recommended treatment methods cannot be performed (due to contraindications), an individualized treatment plan must be drawn up. General contraindications: cases of severe decompensated somatic diseases where the risk of life-threatening complications during treatment outweighs the risk of breast cancer progression. The choice of surgical procedure is determined by the need to adhere to the principles of ablastics, taking into account the feasibility of radiation therapy (RT) and drug therapy, as well as the patient's preference.

It is advisable for the multidisciplinary team including a surgeon, oncologist, and radiation therapist to formulate the systemic (drug) therapy plan taking into account the extent of the disease (stage) and the biological subtype of the tumor (see sections 3.2 and 3.4) [49].

Comment: dose calculation within the specified target should be performed taking into account the tolerance of normal tissues [52]. The dose to the heart, contralateral breast, lungs, and other normal tissues should be kept to a minimum. Dose variations within the planned treatment volume should not exceed 7%, and 95% of the planned treatment volume must receive at least 95% of the prescribed dose, according to the recommendations of the International Commission on Radiation Units and Measurements (ICRU) reports 50, 62, and 83. The volume of breast tissue receiving more than 105% of the prescribed dose should be minimized [53].

For adequate local control, 3D conformal radiation therapy should preferably be delivered using linear electron accelerators with multileaf collimators using 6 or 18 MV photons, electrons of various energies, or a proton accelerator using a 70-230 MeV proton beam. It is advisable to regularly verify patient positioning and treatment plans on the radiation therapy unit [53].

In the absence of linear electron accelerators, external beam radiation therapy should be performed on teletherapy gamma-ray units for adequate local control [53].

Comments: it is not recommended to start radiation therapy on a Friday and finish on a Monday, as this reduces the effectiveness of the therapy.

Clinical stages of breast cancer:

• early operable (resectable) breast cancer (stages 0, I, IIA, IIB, IIIA (T3N1M0));
• locally advanced (initially inoperable/unresectable) breast cancer (stages IIIA (except T3N1M0), IIIB, IIIC);
• metastatic breast cancer or disease recurrence.

The algorithm for therapeutic and diagnostic measures for various stages and clinical groups of breast cancer is presented in Fig. 1, 2.

3.2. Early operable breast cancer (stages 0, I, IIA, IIB, IIIA)

3.2.1. Stage 0 (TisN0M0), ductal carcinoma in situ

Comment: if necessary, urgent intraoperative pathomorphological (including cytological) examination of the resection margins is advisable.

• If tumor elements are detected in the resection margins, a repeat surgery—reresection or mastectomy—is recommended to achieve clear resection margins in order to ensure local disease control [56, 57].

Leveled ALevel 3Grade of Recommendation – A (Level of Evidence – 3).

Comments: margins are considered "clear" if there is no non-invasive carcinoma at a distance of >2 mm from the resection margin [56, 57].

Comments: the use of 5 or more clips provides optimal visualization of the area for subsequent radiation therapy.

Comment: when performing skin-sparing/nipple-sparing mastectomy, histological examination of the duct margins transected behind the nipple is mandatory. Detection of tumor elements in this zone is an indication for removal of the nipple-areola complex. If necessary, a symmetrizing operation on the contralateral breast can be performed.

• If technically unfeasible to perform SLNB, it is recommended to perform axillary lymphadenectomy (Level I) to ensure optimal local control [61].

GCR CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: if an invasive component is suspected in the breast tumor, it is advisable to perform SLNB.

Comments: to ensure optimal local control after breast-conserving surgery, indications for radiation therapy should be determined by a multidisciplinary team including a surgeon and a radiation oncologist, based on the individual risk of tumor progression. Adjuvant radiation therapy does not affect survival. The entire operated breast should receive a dose of 46-50 Gy in 23-25 fractions or 40-42.5 Gy in 15-16 fractions. Treatment is delivered 5 times a week.

Comments: for adjuvant therapy of in situ carcinoma (ductal or lobular), chemotherapy and ovarian suppression are not indicated.

Comments: for adjuvant therapy of in situ carcinoma (ductal or lobular), chemotherapy and ovarian suppression are not indicated.

3.2.2. Stages I (T1N0M0) and IIA (T2N0M0) (local therapy)

Comment: if necessary, urgent intraoperative pathomorphological (including cytological) examination of the resection margins is advisable.

• If tumor elements are detected in the resection margins, it is recommended to perform a repeat surgery: reresection or mastectomy to achieve clear resection margins [70–73].

GCR CLEL 4Grade of Recommendation – C (Level of Evidence – 4).

Comments: the use of 5 or more clips provides optimal visualization of the area for subsequent radiation therapy.

Comment: if necessary, a symmetry-restoring procedure on the contralateral breast is possible.

Comments: the scope of surgery is determined by the surgeon or oncologist depending on the tumor location and the ratio of tumor size to breast volume. Scope of axillary lymph node dissection: SLNB is preferred. In cases where micrometastases are detected in 1–2 sentinel lymph nodes, lymph node dissection is optional [74]. If routine histological examination reveals a metastasis in one of the examined sentinel lymph nodes, radiotherapy to the axillary region at a dose of 50 Gy can serve as an alternative to axillary lymph node dissection [56].

Comments: the anterior chest wall + ipsilateral regional lymph node drainage areas should receive a dose of 46–50 Gy in 23–25 fractions, treatment is administered 5 days a week. If indicated, a "boost" (additional local radiation) to the postoperative scar area is administered at a dose of 2 Gy per fraction up to a total RT dose of 60 Gy (using electron or photon beams) [54, 76, 77]. In the absence of indications for adjuvant polychemotherapy, the postoperative course of external beam RT is recommended to begin within 12 weeks from the date of surgery, provided the surgical wound has completely healed.

Comments: the entire operated breast should receive a dose of 46–50 Gy in 23–25 fractions or 40–42.5 Gy in 15–16 fractions [54].

In the absence of indications for adjuvant polychemotherapy (PCT), the postoperative course of external beam RT is recommended to begin within up to 16 weeks from the date of surgery, provided the surgical wound has completely healed.

When prescribing adjuvant PCT, radiotherapy is recommended to begin upon completion of all planned polychemotherapy after the recovery of normal blood counts (usually in 3–4 weeks) (regardless of the duration of the chemotherapy course).

The feasibility of radiotherapy to the ipsilateral regional lymph node drainage areas should be considered in patients with node-negative disease with a central/medial tumor location or tumor size greater than 2 cm in the presence of high-risk factors for recurrence (young age, lymphovascular invasion, triple-negative breast cancer subtype).

• Comments: the "boost" can be delivered via external beam RT using electron or photon radiation at a dose of 10–16 Gy in 4–8 fractions, treatment 5 days a week, intraoperatively using electron or photon accelerators, or using low-energy X-rays with a single focal dose of 5–12 Gy, or via interstitial brachytherapy at a dose of 15 Gy, especially in cases where the primary tumor was located deeper than 28 mm from the skin in the breast [81, 83].
• It is recommended that when hormone therapy and/or anti-HER2 therapy is prescribed, RT is administered concurrently with hormone therapy and/or anti-HER2 therapy [54, 80, 84, 85].

GGR ALEL 1Grade of Recommendations — A (Level of Evidence — 1).

Comments: in breast cancer patients older than 70 years with T1N0M0 and estrogen receptor-positive tumor status in the absence of other risk factors, omission of radiotherapy to the remaining breast tissue after breast-conserving surgery may be considered, provided that long-term hormone therapy is administered subsequently [54, 86].

3.2.3. Stages IIA (T1N1M0), IIB (T2N1M0, T3N0M0), IIIA (T3N1M0) (Local Therapy)

Comments: urgent intraoperative pathological (including cytologic) examination of the resection margins may be performed. If necessary, a symmetry-restoring procedure on the contralateral breast is possible. If tumor elements are detected at the resection margins, a repeat operation—re-resection or mastectomy—is recommended to achieve margin clearance.

Comments: the use of 5 or more clips allows for optimal visualization of the area for subsequent radiotherapy.

• If metastatic involvement of the sentinel lymph nodes is detected, it is recommended to perform axillary lymph node dissection to achieve optimal local disease control [90].

GCR ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

Comments: the scope of surgical intervention is determined by the surgeon depending on the tumor location and the ratio of tumor size to breast volume. During lymph node dissection, at the surgeon's discretion, lymph nodes of levels I–II or I–III are removed.

Comments: RT after mastectomy is administered at a dose of 46–50 Gy in 23–25 fractions according to the following indications:

• in case of involvement of 1–3 lymph nodes: to the soft tissues of the anterior chest wall +/– a "boost" to the postoperative scar area at a dose of 10 Gy in 5 fractions, supra-/subclavicular region, ipsilateral parasternal lymph nodes, any part of the axillary region (as a risk zone) (RT may be omitted in patients with 1 positive lymph node in the absence of high-risk factors for tumor recurrence);
• in case of pN₀, tumor size >5 cm: to the soft tissues of the anterior chest wall + regional lymph node drainage areas;
• in case of pN₀, tumor size <5 cm and presence of tumor cells at a distance of <1 mm from the resection margin: consider administering RT to the soft tissues of the anterior chest wall + regional lymph node drainage areas [54, 64, 70].

Comments: RT after breast-conserving surgery is administered in accordance with the following principles:

• in the absence of affected lymph nodes (N₀) only to the remaining part of the breast at a dose of 46-50 Gy in 23-25 fractions or 40-42.5 Gy in 15-16 fractions + a "boost" to the tumor bed (10-16 Gy in 5-8 fractions) according to indications (see above);
• with N0 consider the feasibility of irradiating the operated breast and the supraclavicular and parasternal zones in patients with medial/central tumor location or tumor size >2 cm combined with unfavorable prognostic factors (young age, lymphovascular invasion, fractional dose 2 Gy, total dose 46–50 Gy;
• in case of involvement of 1–3 lymph nodes (N₁) perform RT on the operated breast, supra-/supraclavicular, ipsilateral parasternal and part of the axillary zone (as a high-risk zone) fractional dose 2 Gy, total dose 45–50 Gy;
• the postoperative course of external beam RT, in the absence of adjuvant chemotherapy in the treatment plan, is recommended to start within up to 12 weeks from the date of surgery, provided the surgical wound has completely healed;
• the postoperative course of external beam RT in case of adjuvant chemotherapy is recommended to be initiated after completion of chemotherapy upon recovery of blood count parameters (on average in 3–4 weeks); RT can be administered concurrently with HT and anti-HER2 therapy [54, 90].

When planning subcutaneous or skin-sparing mastectomy with immediate reconstruction, the patient must be consulted by a radiation oncologist before surgery. If there are indications for RT, it is recommended to perform delayed reconstructive surgery after completing the course of RT to reduce the rate of potential complications [80, 87].

3.2.4. Drug therapy (adjuvant/neoadjuvant)

Comments: for small tumors (< 5 mm) combined with N₀, which are prognostically favorable, adjuvant medical therapy has minimal efficacy. The purpose of prescribing adjuvant hormonotherapy (for hormone-dependent tumors) in this situation is the prevention of second (contralateral) hormone-dependent tumors.

When administering adjuvant medical therapy, adhere to the following principles:

• base the adjuvant medical therapy plan on the tumor's molecular subtype (Tables 2, 3) [37];
• start adjuvant medical therapy with chemotherapy if indicated; chemotherapy with taxanes is recommended to be administered concurrently with anti-HER2 therapy if indicated [37];
• adjuvant ET, if indicated, is recommended to be started after the completion of chemotherapy and administered concurrently with anti-HER2 therapy and RT if indicated;
• adjuvant RT, if indicated, is recommended to be started after the completion of chemotherapy and administered concurrently with ET and anti-HER2 therapy if indicated [37];
• when administering chemotherapy, use standard regimens while maintaining the recommended dose intensity, and avoid unjustified dose reductions (in the absence of toxicity) and increases in intervals between courses [36];
• when administering chemotherapy, use sequential (rather than concurrent!) administration of anthracyclines and related compounds and taxanes; when prescribing paclitaxel**, weekly administration is preferable, especially in triple-negative breast cancer [92].

The sequence of various adjuvant therapy methods is shown in Fig. 3 [37].

Table 2. Surrogate determination of molecular subtypes of breast cancer [36, 37]

Notes:

¹The Ki67 value should be assessed based on the experience of the local pathomorphology laboratory: for example, if the median Ki67 value in hormone-dependent breast cancer is 20% in a given laboratory, a value of ≤10% should be regarded as unambiguously low, and ≥30% as unambiguously high; for Ki67 levels between 20% and 30%, other clinical and morphological prognostic factors (stage, grade, morphological variant, etc.) should be taken into account when deciding on treatment tactics [93];

²the threshold value for PR determination is considered to be 20% [94].

Table 3. Recommended algorithm for adjuvant systemic therapy depending on the molecular biological subtype and stage of breast cancer [38, 95–97]

Table 4. Recommended adjuvant chemotherapy regimens for HER2-negative breast cancer [38, 92, 95–97, 108, 110–114]

¹doxorubicin** may be substituted with #epirubicin** at a cycle dose of 90 mg/m² (EC regimen [115]);

²prophylactic administration of granulocyte colony-stimulating factor (G-CSF) is required: #filgrastim** 5 mcg/kg subcutaneously (SC) 24–72 hours after the end of chemotherapy administration and until recovery of normal neutrophil count after nadir, or #pegfilgrastim** at a dose of 6 mg, or #empegfilgrastim** at a dose of 7.5 mg subcutaneously as a single dose at least 24 hours after the end of chemotherapy administration [95, 116–118];

³dose-dense chemotherapy should be considered in rapidly proliferating (high Ki67) breast cancer subtypes;

⁴when using weekly paclitaxel administration, standard premedication volume may be reduced (at the discretion of the treating physician) according to the following schedule: cycles 1–2: dexamethasone 10 mg IM or orally 12 and 6 hours before paclitaxel administration, H1 receptor blockers (diphenhydramine 50 mg or equivalent doses of analogues) IV bolus 30–60 minutes before paclitaxel administration, H2 receptor blockers (famotidine 50 mg or equivalent doses of analogues) IV bolus 30–60 minutes before paclitaxel administration. In the absence of hypersensitivity reactions during the first two cycles, subsequent administration of dexamethasone 8 mg IV 30–60 minutes before paclitaxel administration is possible, with H1/H2 histamine receptor blockers administered only in case of prior hypersensitivity reactions. Paclitaxel may be administered at ANC ≥1.0×10⁹/L and platelet count ≥100.0×10⁹/L [119];

⁵the administration schedule of paclitaxel** 175 mg/m² every 3 weeks is less effective, particularly in triple-negative breast cancer [92];

⁶in case of contraindications to the administration of anthracyclines, related compounds, and taxanes;

⁷in patients with triple-negative breast cancer (negative ER, PR, and HER2) who received neoadjuvant CT with anthracyclines and related compounds and taxanes in standard volume, in the presence of invasive residual disease according to the above recommendation [108].

Comments: if ado-trastuzumab emtansine administration is discontinued prematurely due to toxicity, trastuzumab administration should be continued to reach a total duration of anti-HER2 therapy of 1 year, including the preoperative phase [114].

Table 5. Recommended adjuvant drug therapy regimens for HER2-positive breast cancer [54, 95, 104, 106, 109, 120–123]

Notes:

¹doxorubicin** may be replaced by #epirubicin** at a course dose of 90 mg/m² (EC regimen) [115]; simultaneous administration of anthracyclines and related compounds (doxorubicin** and #epirubicin**) and anti-HER2 agents (trastuzumab**, pertuzumab**) is not recommended due to a high risk of cardiotoxicity; before and during therapy with anthracyclines and related compounds and/or trastuzumab**, LVEF monitoring using echocardiography is required at a frequency of once every 3 weeks (or more often if indicated);

²administration of anti-HER2 agents (trastuzumab**, pertuzumab**) should preferably be initiated concurrently with a non-anthracycline taxane-containing regimen;

³it is possible to use the subcutaneous formulation of trastuzumab** at a dose of 600 mg/5 ml (regardless of the patient's body weight) once every 3 weeks; a loading dose is not required [125, 126];

⁴the duration of adjuvant #trastuzumab** therapy is 12 months, including the preoperative phase if neoadjuvant therapy is administered; the total duration of #trastuzumab** use must not exceed 12 months, including the duration of preoperative therapy;

⁵when using weekly paclitaxel infusions, the standard premedication volume can be reduced (at the discretion of the attending physician) and administered according to the following schedule: cycles 1–2 – dexamethasone 10 mg IM or orally 12 and 6 hours before paclitaxel administration, H1 receptor blockers (diphenhydramine 50 mg or equivalent doses of analogues) IV bolus 30–60 minutes before paclitaxel administration, H2 receptor blockers (famotidine 50 mg or equivalent doses of analogues) IV bolus 30–60 minutes before paclitaxel administration. In the absence of hypersensitivity reactions during the first two cycles, subsequent administration of dexamethasone 8 mg IV 30–60 minutes before paclitaxel is possible, while H1/H2 histamine receptor blockers should be administered only if hypersensitivity reactions occurred previously. Paclitaxel administration may be performed with an ANC ≥1.0 × 10⁹/l and a platelet count ≥100.0 × 10⁹/l [119];

⁶it is advisable to consider this regimen for T1b,c (>5 mm, but ≤20 mm) and N0;

⁷prophylactic administration of G-CSF is indicated: #filgrastim** 5 mcg/kg subcutaneously (SC) 24–72 hours after the completion of chemotherapy infusions and until neutrophil counts recover to normal levels following the nadir, or #pegfilgrastim** at a dose of 6 mg or #empegfilgrastim** at a dose of 7.5 mg subcutaneously, once, no earlier than 24 hours after the completion of chemotherapy infusions [95, 116–118];

⁸a dose-dense chemotherapy regimen should be considered for rapidly proliferating breast cancer variants (with high Ki67);

⁹ regimen is indicated when the following features are combined: no neoadjuvant systemic therapy was administered, N≥2; pertuzumab** is administered in combination with trastuzumab** for 12 months;

¹⁰ is recommended for patients who have received standard neoadjuvant CT with anthracyclines and/or taxanes and trastuzumab** (± pertuzumab**) in full, in the presence of an invasive residual tumor according to the recommendation above [114].

Comments: tumors are considered hormone-dependent with detectable ER and/or PR expression in ≥1% of invasive breast cancer cells [17]. The choice of HT regimen depends on ovarian function (see Table 6, 7).

Table 6. Medications recommended for adjuvant hormone therapy of breast cancer

Notes:

¹can be used regardless of ovarian function; ovarian suppression in addition to antiestrogens is recommended for patients with preserved ovarian function in the presence of high-risk features for recurrence (see Table 7); testing for CYP2D6 gene mutations to decide on tamoxifen** administration is not recommended in routine practice;

²indicated for use only in postmenopausal patients; in patients with preserved ovarian function, ovarian suppression is required for the administration of aromatase inhibitors;

³indicated for use only in patients with preserved ovarian function when ovarian suppression is necessary; prescribed in combination with antiestrogens or aromatase inhibitors; gonadotropin-releasing hormone (GnRH) agonists are recommended to be administered once every 28 days.

Table 7. Recommended adjuvant hormone therapy regimens for breast cancer depending on ovarian function

Notes:

¹unfavorable prognostic factors include T3−4, N+, G3, HER2 overexpression/amplification, high Ki67, pronounced lymphovascular invasion;

²recommended duration of ovarian suppression is 5 years;

³ovarian suppression is required throughout the entire duration of aromatase inhibitor therapy;

⁴in intermediate prognosis (T2N0 and G2), if ovarian suppression is prescribed (in combination with tamoxifen** or aromatase inhibitors), adjuvant chemotherapy may be omitted.

Tamoxifen** can be used both in menopausal patients and in those with preserved ovarian function.

Aromatase inhibitors are contraindicated in patients with preserved ovarian function and can only be prescribed to patients who have reached sustained physiological menopause (see menopause criteria) or who are receiving ovarian suppression. Aromatase inhibitor therapy is associated with a lower incidence of thromboembolic events and endometrial cancer, and a higher incidence of osteoporosis (and associated bone fractures) and cardiovascular complications compared to tamoxifen**. Third-generation aromatase inhibitors (letrozole, anastrozole**, exemestane) are equally effective.

Menopause criteria [54]:

• bilateral oophorectomy;
• age ≥60 years;
• age <60 years:

• in the absence of chemotherapy, hormone therapy with tamoxifen** or toremifene, and OS: amenorrhea for ≥12 months combined with postmenopausal FSH and estradiol levels;
• during therapy with tamoxifen** or toremifene: postmenopausal FSH and estradiol levels.

If ovarian function is preserved at the start of chemotherapy (neo-/adjuvant), amenorrhea is not a sufficient sign of achieving menopause, and prescribing drugs approved only for menopausal patients requires ovarian suppression by any available method or regular determination of FSH and estradiol levels.

The following methods can be used to achieve ovarian suppression:

• medical (GnRH agonists; see Table 6):

• causes reversible suppression of ovarian function;
• does not always ensure complete suppression of ovarian function, especially in young women; to confirm complete ovarian suppression, serum estradiol determination is necessary, especially in women receiving aromatase inhibitors; determining FSH during GnRH agonist treatment is uninformative; initiation of aromatase inhibitor therapy should begin 6−8 weeks after the first administration of GnRH agonists;
• GnRH analogues are recommended to be administered monthly;

• surgical (bilateral oophorectomy); causes irreversible cessation of ovarian function;

• radiation; causes irreversible cessation of ovarian function (least preferred option).

The optimal method of ovarian suppression has not been defined.

Comment: neoadjuvant medical therapy is administered provided all of the following conditions are met:

• proven invasive initially operable breast cancer (T2N0M0, T2N1M0, T3N0M0, T3N1M0);

• • • triple-negative phenotype or HER2-positive status in order to perform breast-conserving surgery, as well as to determine prognosis and administer additional adjuvant therapy in the presence of residual tumor;
    • may be considered in patients with high-risk luminal B cancer (G3, high Ki67) if there are clear indications for this volume of chemotherapy and the patient desires breast-conserving surgery;

• presence of all criteria, except for tumor node size, indicating the feasibility of breast-conserving surgery;
• patient's consent to perform breast-conserving surgery; the patient must be informed about the need for radiation therapy in case of breast-conserving treatment, as well as the likelihood of re-operation if residual tumor is found in the resection margins;
• absolute indications for this type of medical therapy based on preoperative examination results; if information is insufficient (e.g., tumor node size, axillary lymph node status, presence of invasive component in ductal carcinoma in situ), surgical treatment with examination of the removed tumor and pathomorphological staging is recommended at the first stage.

Comments: the sequence of medical and surgical treatment does not affect relapse-free and overall survival. Neoadjuvant medical therapy for initially operable breast cancer allows to:

• perform breast-conserving surgery and improve cosmetic outcome;
• identify patients with a more favorable prognosis (in case of achieving a complete pathomorphological response) and individualize adjuvant therapy;
• evaluate the effect of medical therapy and timely discontinue it in case of progression (with surgical treatment performed).

Comments: radiolabeled and/or radioactive markers or tattooing can be used for marking.

Table 8. Recommended neoadjuvant medical therapy regimens for breast cancer [36, 95–97]

Notes:

¹doxorubicin** may be replaced by epirubicin** at a course dose of 90 mg/m² (EC regimen) [115];

²When using weekly #paclitaxel** administrations, the volume of standard premedication can be reduced (at the discretion of the attending physician) and administered according to the following schedule: cycles 1-2 – dexamethasone 10 mg IM or orally 12 and 6 hours before paclitaxel administration, H1 receptor blockers (diphenhydramine 50 mg or equivalent doses of analogues) IV bolus 30-60 minutes before paclitaxel administration, H2 receptor blockers (famotidine 50 mg or equivalent doses of analogues) IV bolus 30-60 minutes before paclitaxel administration. In the absence of hypersensitivity reactions during the first two cycles, subsequent administration of dexamethasone 8 mg IV 30-60 minutes before paclitaxel administration is possible, while H1/H2 histamine receptor blockers should be administered only in case of prior hypersensitivity reactions. Paclitaxel can be administered at an ANC ≥1.0 × 10⁹/L and a platelet count ≥100.0 × 10⁹/L [119];

³a dose-dense chemotherapy regimen should be considered for rapidly proliferating (high Ki67) breast cancer variants [160];

⁴prophylactic administration of G-CSF is indicated: #filgrastim** 5 mcg/kg subcutaneously (SC) 24-72 hours after the end of chemotherapy administration and until neutrophil counts normalize after the nadir, or #pegfilgrastim** at a dose of 6 mg or #empegfilgrastim** at a dose of 7.5 mg subcutaneously, once, no earlier than 24 hours after the end of chemotherapy administration [95, 116–118];

⁵regimens containing platinum compounds can be used for the triple-negative phenotype;

⁶in case of contraindications to the administration of anthracyclines, related compounds, and taxanes;

⁷simultaneous administration of anthracyclines and related compounds (doxorubicin**, epirubicin**) and anti-HER2 drugs (#trastuzumab**, #pertuzumab**) is not recommended due to the high risk of cardiotoxicity; before and during therapy with anthracyclines, related compounds, and/or trastuzumab, LVEF monitoring via echocardiography is required once every 3 months (or more frequently if indicated) [161];

⁸administration of anti-HER2 drugs (trastuzumab**, pertuzumab**) should begin concurrently with a non-anthracycline taxane-containing regimen;

⁹it is possible to use the subcutaneous formulation of trastuzumab** at a dose of 600 mg/5 mL (regardless of the patient's body weight) once every 3 weeks; a loading dose is not required [125, 126];

¹⁰the regimen can be used as neoadjuvant therapy for tumors ≥T2 or N+.

Comments: basic principles of neoadjuvant medical therapy:

• drugs and regimens with the highest expected efficacy should be used;
• all required courses of chemotherapy are recommended to be administered before surgery, as this increases the likelihood of achieving a pathological complete response [23];
• if all planned courses of chemotherapy are administered before surgery, adjuvant chemotherapy is not recommended; if for any reason it was not possible to complete all planned courses of chemotherapy in the preoperative stage, the remaining courses are recommended to be administered after surgery; in breast cancer patients with a triple-negative phenotype (negative ER, PR, and HER2) who received full-dose neoadjuvant chemotherapy with anthracyclines, related compounds, and taxanes, in the presence of residual tumor, it is recommended to consider prescribing adjuvant chemotherapy with #capecitabine** (2000 mg/m² orally on days 1–14 every 3 weeks for 6 months) [108]; in patients with HER2-positive breast cancer – trastuzumab emtansine** (3.6 mg/kg IV on day 1 once every 3 weeks, up to 14 cycles) [114];
• the optimal time interval from the start of treatment to response assessment depends on the type of treatment, but should not exceed 6–8 weeks. Response assessment is recommended using physical examination and instrumental methods that documented pathological changes in the breast and regional areas before treatment initiation;
• upon obtaining a "rapid" (as a result of 2–4 courses of chemotherapy) clinical response, it is not recommended to reduce the volume of chemotherapy to fewer than 6-8 courses;
• in the absence of sufficient financial resources guaranteeing standard neoadjuvant medical therapy (anthracyclines and related compounds, taxanes, trastuzumab**, pertuzumab**, G-CSF if indicated), it is recommended to perform surgical treatment at the first stage.

• • drugs affecting bone structure and mineralization (bisphosphonates) (#zoledronic acid** 4 mg IV once every 6 months) for 2–3 years (depending on bone mineral density);
  • cholecalciferol 400-800 IU/day orally daily + calcium carbonate 500-1000 mg/day orally daily long-term [162].

GCR CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

3.3. Locally advanced primarily inoperable invasive breast cancer

3.3.1. Drug therapy

Comment: it is advisable to administer aromatase inhibitor therapy for 4–8 months or until maximum effect is achieved.

Comments: in case of premature discontinuation of trastuzumab emtansine due to toxicity, trastuzumab administration should be continued until a total duration of anti-HER2 therapy of 1 year is reached, including the preoperative stage [114].

3.3.2. Surgical treatment

Comments: The scope of the surgical intervention is determined by the surgeon based on tumor location and the ratio of tumor volume to breast volume. Consideration should be given to performing skin-sparing or nipple-sparing mastectomy with axillary, subscapular, and subclavicular lymphadenectomy, with immediate or delayed reconstruction. If the tumor invades the pectoralis major muscle, a partial resection of the muscle is performed. If necessary, the defect is reconstructed with a transposed myocutaneous flap.

The method and timing of reconstruction are determined by a multidisciplinary team consisting of a surgeon/plastic surgeon and a radiation oncologist, taking into account the need for radiotherapy (RT); if indications for RT are present, it is recommended to perform delayed reconstructive plastic surgery after completion of the RT course.

3.3.3. Radiation therapy

Comments: RT should be initiated 4–12 weeks after surgery (provided the surgical wound is completely healed); in cases of adjuvant chemotherapy, it should be initiated 3–4 weeks after its completion.

Comments:

• supraclavicular/subclavicular regions and the chain of ipsilateral parasternal lymph nodes: SDD (single daily dose) 2 Gy, TDD (total dose) 48–50 Gy;
• a "boost" to the surgical scar or tumor bed up to a TDD of 60 Gy for the entire course of treatment;
• in the presence of residual metastases in supraclavicular or subclavicular lymph nodes - a TDD of 60–64 Gy for the entire course of RT (ultrasound or CT imaging is required when selecting local radiation fields);
• if the tumor invades the skin of the breast, it is advisable to administer RT using tissue-equivalent boluses to ensure adequate dose distribution.

Comments: RT is administered 2 to 4 weeks after the completion of medical therapy, and may be administered concurrently with medical therapy (following a multidisciplinary team conference comprising a radiation oncologist, surgeon, and oncologist).

Comments: following RT to the breast and lymph node drainage areas, treatment efficacy must be assessed and treatment tactics re-discussed at a multidisciplinary team meeting consisting of a surgical oncologist and a radiation oncologist. If surgical treatment is feasible, radical mastectomy is preferred [49].

Comment: the total dose for the entire course of treatment to the breast is 60–66 Gy, and locally to the tumor up to 60–70 Gy (65–70 Gy) depending on the number of courses and the efficacy of prior chemotherapy; locally to specific identifiable metastatic lymph nodes up to 60–66 Gy at a fractional dose of 2 Gy. Selection of local radiation fields requires ultrasound or CT imaging [49]. Depending on the specific clinical situation, the fractional dose may be increased to 2.5 Gy, taking into account the recalculation of total isoeffect doses.

3.4. Recurrent and metastatic breast cancer

3.4.1. Treatment of isolated local recurrences

To reduce the risk of breast cancer recurrence and death following the removal of an isolated local recurrence, systemic therapy is carried out in accordance with the following principles [37]:

• • for triple-negative phenotype – adjuvant chemotherapy (the cumulative dose of anthracyclines and related compounds must be taken into account if they were previously administered);
  • for luminal HER2-negative phenotype – adjuvant endocrine therapy only; the choice of drug is determined by prior endocrine therapy, if any, and ovarian function;
  • for HER2-positive phenotype – chemotherapy + anti-HER2 therapy ± endocrine therapy (depending on ER and PR expression levels);
  • consider prescribing RT in all cases where it has not been previously administered, as well as when there is an opportunity for additional safe irradiation of the affected area.

Comments: the choice of systemic therapy option should be individualized, taking into account the immunophenotype of the primary and recurrent tumors, prior adjuvant treatment, duration of remission, and the patient's general condition, including residual toxicities from previous treatments.

3.4.2. Treatment of disseminated breast cancer

Comments: there is no single standard of treatment for metastatic breast cancer. The mainstay of treatment is systemic therapy, which includes chemotherapy and/or endocrine therapy, which should be supplemented with targeted therapy according to indications.

Comments: progression of the metastatic process in the bones is not an indication for discontinuation of bone-modifying agents. Switching from bisphosphonate therapy to denosumab** therapy is advisable in the following clinical situations: inability to prescribe or continue bisphosphonate therapy due to impaired renal function; inefficacy of bisphosphonate therapy (development of new multiple bone complications, worsening of pain syndrome, etc.); inability to perform intravenous infusions.

Comments: exceptions are rapidly progressing variants of breast cancer accompanied by a visceral crisis, including those developed during prior lines of hormone therapy, as well as hormone-resistant cases. Signs of a visceral crisis include multiple metastatic lesions in internal organs; clinical and/or laboratory signs of internal organ dysfunction that pose a threat to the patient's life and require rapid achievement of an antitumor effect.

Comments: scintigraphy should be performed every 4-6 months; PET-CT and tumor marker determination are optional [54].

Comments: in individual cases (e.g., when the patient refuses ovarian suppression), selective estrogen receptor modulators are prescribed (see Table 9).

Comments: when choosing an endocrine therapy option, ovarian function, prior endocrine therapy and its efficacy, and comorbid conditions should be taken into account. The algorithm for hormone therapy in postmenopausal patients is presented in Fig. 7.

Table 9. Recommended endocrine agents and hormone therapy regimens for metastatic HER2-negative breast cancer [16, 36–38, 180–196]

Notes:

¹only for patients with preserved ovarian function when ovarian suppression is necessary; prescribed in combination with other endocrine therapy agents (selective estrogen receptor modulators, estrogen receptor antagonists, aromatase inhibitors, progestogens); GnRH analogues are recommended to be administered once every 28 days;

²for premenopausal and postmenopausal patients; determination of CYP2D6 gene mutations to decide on the administration of tamoxifen** in routine practice is not recommended;

³only for postmenopausal patients; in patients with preserved ovarian function, ovarian suppression (administration of GnRH analogues or oophorectomy) is required;

⁴if toxicity develops, dose reduction of palbociclib** to 100 mg/day and 75 mg/day, ribociclib** to 400 mg/day and 200 mg/day, and abemaciclib** to 200 mg/day and 100 mg/day orally (in two doses) is recommended (see instructions for medical use of the drugs);

⁵for patients in satisfactory general condition, with normal internal organ function (including normal blood glucose levels) in the presence of signs of resistance to non-steroidal aromatase inhibitors (progression during adjuvant or therapeutic treatment with letrozole/anastrozole** or within 12 months after completion of these drugs ± one line of chemotherapy); there are no data on the efficacy of another line of endocrine therapy including everolimus** upon progression during therapy with exemestane and everolimus**;

⁶upon progression during endocrine therapy and one or more lines of chemotherapy;

⁷if toxicity develops, dose reduction of abemaciclib** to 300 mg/day, 200 mg/day, and 100 mg/day orally (in two doses) is possible (see instructions for medical use of the drug);

⁸the combination of cyclin-dependent kinase 4/6 inhibitors with aromatase inhibitors or fulvestrant** is the preferred option for 1st and 2nd lines of treatment, given the significant progression-free survival benefit and acceptable toxicity profile;

⁹The combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib with fulvestrant** is recommended in the presence of PIK3CA mutations for patients with advanced hormone receptor-positive, HER2-negative breast cancer upon progression on mono- or combination endocrine therapy. Alpelisib should not be prescribed to patients with type 1 diabetes mellitus or uncontrolled type 2 diabetes mellitus. Prior to initiating alpelisib, fasting plasma glucose and HbA1c (glycated hemoglobin) levels must be determined. If HbA1c >7.0%, an endocrinologist consultation is required before prescribing alpelisib therapy;

¹⁰if toxicity develops, a dose reduction of alpelisib to 250 mg/day or 200 mg/day is possible (see the product prescribing information).

• Breast cancer with negative ER and PR;
• Luminal breast cancer resistant to endocrine therapy;
• Luminal breast cancer with signs of visceral crisis [34, 35].

GCR CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: There is no standard first-line chemotherapy for recurrent and metastatic breast cancer. The choice of regimen should be individualized, taking into account tumor characteristics and the clinical and anamnestic features of the patient, as well as the composition and efficacy of previous, including adjuvant/neoadjuvant, chemotherapy, if administered.

Table 10. Chemotherapy regimens recommended for recurrent and metastatic breast cancer [24]

Notes:

¹the total cumulative dose of anthracyclines and related compounds, taking into account all lines of therapy including adjuvant therapy, must not exceed 450-500 mg/m² for doxorubicin** and 900 mg/m² for epirubicin**;

²before and during therapy with anthracyclines and related compounds, left ventricular ejection fraction (LVEF) monitoring via echocardiography (EchoCG) is required once every 3 months (or more frequently if indicated);

³weekly paclitaxel administration is preferred**; when using weekly paclitaxel administration, the volume of standard premedication can be reduced (at the discretion of the attending physician) and carried out according to the following regimen: cycles 1-2 – dexamethasone 10 mg IM or orally 12 and 6 hours before paclitaxel administration, H1 receptor blockers (diphenhydramine 50 mg or equivalent doses of analogues) IV bolus 30-60 minutes before paclitaxel administration, H2 receptor blockers (famotidine 50 mg or equivalent doses of analogues) IV bolus 30-60 minutes before paclitaxel administration. In the absence of hypersensitivity reactions during the first two cycles, subsequent administration of dexamethasone 8 mg IV 30-60 minutes before paclitaxel administration is possible, and the administration of H1/H2 histamine receptor blockers – only in case of prior hypersensitivity reactions. Paclitaxel administration can be performed with ANC ≥1.0 × 10⁹/L and a platelet count of ≥100.0 × 10⁹/L [119];

⁴recommended for HER2-negative breast cancer, including triple-negative breast cancer;

⁵for patients with triple-negative breast cancer as first-line treatment when Ventana SP142 testing establishes PD-L1 expression on ≥1% of immunocompetent cells;

⁶if prior therapy with taxanes and anthracyclines and related compounds is ineffective; this regimen should not be prescribed if ALT/AST is elevated more than 2.5 times the upper limit of normal (ULN) and/or bilirubin is above the ULN.

⁷recommended for HER2-negative breast cancer in adult patients with germline BRCA mutations who have previously received neoadjuvant or adjuvant chemotherapy or chemotherapy for metastatic disease.

Comments: there are no standard approaches to second and subsequent lines of chemotherapy, nor any data indicating the advantages of a particular drug or regimen. Continuation of chemotherapy after the third line may be discussed for patients in a satisfactory general condition who have responded to previous lines of chemotherapy.

Comments: the regimen may be recommended for patients who have not received pertuzumab** in the neo-/adjuvant setting, as well as those who have received pertuzumab** in the neo-/adjuvant setting, if at least 1 year has passed from the completion of pertuzumab** therapy to disease progression.

Table 11. Drug therapy regimens for HER2-positive recurrent and metastatic breast cancer

Notes:

¹trastuzumab** subcutaneous formulation may be used at a dose of 600 mg / 5 mL (regardless of the patient's body weight) once every 3 weeks; a loading dose is not required [125, 126];

²monitoring of LVEF using echocardiography is required before and during trastuzumab** therapy at a frequency of once every 3 weeks (or more frequently if indicated);

³when using weekly paclitaxel infusions, the volume of standard premedication can be reduced (at the discretion of the attending physician) and administered according to the following schedule: cycles 1-2: dexamethasone 10 mg IM or orally 12 and 6 hours before paclitaxel infusion, H1 receptor blockers (diphenhydramine 50 mg or equivalent doses of analogues) IV bolus 30–60 minutes before paclitaxel infusion, H2 receptor blockers (famotidine 50 mg or equivalent doses of analogues) IV bolus 30-60 minutes before paclitaxel infusion. In the absence of hypersensitivity reactions during the first two cycles, subsequent administration of dexamethasone 8 mg IV 30-60 minutes before paclitaxel infusion is possible, while H1/H2 histamine receptor blockers should be administered only in case of prior hypersensitivity reactions. Paclitaxel infusion may be performed with an ANC ≥1.0 × 10⁹/L and a platelet count of ≥100.0 × 10⁹/L.

⁴increasing the number of docetaxel** cycles beyond 6 does not lead to an improvement in disease-free and overall survival [241];

⁵the regimen can be recommended for patients who have not received pertuzumab** in the neo-/adjuvant setting, as well as those who have received pertuzumab in the neo-/adjuvant setting, provided that at least 1 year has passed from the completion of pertuzumab therapy to disease progression;

⁶for patients who received trastuzumab**;

⁷in the absence of signs of visceral crisis;

⁸all drugs are used in standard doses and regimens; aromatase inhibitors and #fulvestrant** can be prescribed to postmenopausal women.

Comments: scintigraphy should be performed every 4 cycles, while PET-CT and tumor marker level determination are optional [54].

Comments: there are no standard approaches to the use of these treatment methods in recurrent and metastatic breast cancer.

3.5. Pain management

The principles of pain management and the optimal selection of analgesic therapy in breast cancer patients with chronic pain syndrome correspond to the pain management principles outlined in the clinical guidelines "Chronic pain syndrome in adult patients requiring palliative medical care".

3.6. Monitoring during treatment. Response evaluation

To assess the effect and complications (toxicity) of drug therapy, it is necessary to monitor the patient during treatment and make necessary adjustments (change of regimen, dose reduction, discontinuation of treatment, prescription of symptomatic therapy, etc.).

To assess the efficacy and complications (toxicity) of drug therapy, it is advisable to conduct periodic examinations and assessments of various symptoms, laboratory data (primarily complete blood count and liver enzymes), and the results of instrumental examinations in accordance with the following schedule: during chemotherapy, examination, symptom assessment, and laboratory data analysis are performed before each cycle, whereas during hormone therapy—every 1–3 months; instrumental examinations during chemotherapy should be performed every 2–4 cycles, and during hormone therapy—every 2–3 months. The intervals between examinations may be altered depending on the specific clinical situation [38]. Performing PET-CT and determining tumor marker levels is not mandatory.

The results of examination and evaluation are classified as follows:

• objective response: significant reduction in the size and/or number of tumor lesions; is an indication to continue ongoing therapy in the absence of severe toxicity;
• disease stabilization: absence of significant changes in the size and number of tumor lesions; with a satisfactory general condition and good tolerability, treatment may be continued;
• disease progression is an indication to change treatment.

If disease progression is suspected based on examination findings, confirmatory examinations must be performed, including the evaluation of areas not examined before the start of therapy.

Signs of progression are:

• • appearance and/or worsening of symptoms caused by tumor growth (e.g., pain or dyspnea);
  • significant increase in size or appearance of new tumor lesions detected upon examination;
  • deterioration of general condition (to be differentiated from treatment toxicity);
  • unmotivated weight loss (to be differentiated from treatment toxicity);
  • elevation of ALP, ALT, AST, bilirubin (to be differentiated from treatment toxicity);
  • hypercalcemia.

Appearance of new and/or significant enlargement of previously existing lesions according to objective imaging methods; when evaluating radioisotope imaging data (bone scan, positron emission tomography (PET)), it should be borne in mind that bone metastasis repair—initiated as a result of effective antitumor therapy (in combination with agents affecting bone structure and mineralization) and accompanied by increased metabolism—may create a false picture of progression due to the appearance of new lesions on scans and increased radiopharmaceutical uptake in existing lesions, especially during the first follow-up evaluation [36–38].

3.7. Supportive care in breast cancer patients

The principles of treatment and prevention of nausea and vomiting in breast cancer patients correspond to the principles outlined in the recommendations "Practical guidelines for the prevention and treatment of nausea and vomiting in cancer patients" (authors: Vladimirova L.Yu., Gladkov O.A., Koroleva I.A., Rumyantsev A.A., Semiglazova T.Yu., Tryakin A.A. Malignant tumors: Practical guidelines RUSSCO #3s2, 2020 (vol. 10).37, https://rosoncoweb.ru/standarts/RUSSCO/2020/2020-37.pdf).

The principles of treatment and prevention of bone complications in breast cancer patients correspond to the principles outlined in the methodological guidelines "Use of osteomodifying agents for the prevention and treatment of bone pathology in malignant neoplasms" (authors: Bagrova S.G., Kopp M.V., Kutukova S.I., Manzyuk L.V., Semiglazova T.Yu. Malignant tumors: Practical guidelines RUSSCO #3s2, 2020 (vol. 10).38, https://rosoncoweb.ru/standarts/RUSSCO/2020/2020-38.pdf).

The principles of prevention and treatment of infectious complications and febrile neutropenia in breast cancer patients correspond to the principles outlined in the methodological guidelines "Practical guidelines for the diagnosis and treatment of febrile neutropenia" (authors: Sakaeva D.D., Kurmukov I.A., Orlova R.V., Shabaeva M.M. Malignant tumors: Practical guidelines RUSSCO #3s2, 2020 (vol. 10).39, https://rosoncoweb.ru/standarts/RUSSCO/2020/2020-39.pdf).

The principles of prevention and treatment of hepatotoxicity in breast cancer patients correspond to the principles outlined in the methodological guidelines "Clinical guidelines for the correction of hepatotoxicity induced by antitumor therapy" (authors: Tkachenko P.E., Ivashkin V.T., Maevskaya M.V. Malignant tumors: Practical guidelines RUSSCO #3s2, 2020 (vol. 10).40, https://rosoncoweb.ru/standarts/RUSSCO/2020/2020-40.pdf).

The principles of prevention and treatment of cardiovascular complications in breast cancer patients correspond to the principles outlined in the methodological guidelines "Practical guidelines for the correction of cardiovascular toxicity of antitumor drug therapy" (authors: Vitsenya M.V., Ageev F.T., Gilyarov M.Yu., Ovchinnikov A.G., Orlova R.V., Poltavskaya M.G. Malignant tumors: Practical guidelines RUSSCO #3s2, 2020 (vol. 10).41, https://rosoncoweb.ru/standarts/RUSSCO/2020/2020-41.pdf).

The principles of prevention and treatment of skin complications in breast cancer patients correspond to the principles outlined in the guidelines "Practical Guidelines for the Medical Treatment of Dermatological Reactions in Patients Receiving Antineoplastic Drug Therapy" (authors: Koroleva I.A., Bolotina L.V., Gladkov O.A., Gorbunova V.A., Kruglova L.S., Manzyuk L.V. et al. Malignant Tumors: Practical Guidelines RUSSCO #3s2, 2020 (vol. 10).42, https://rosoncoweb.ru/standarts/RUSSCO/2020/2020-42.pdf).

The principles of nutritional support in breast cancer patients correspond to the principles outlined in the guidelines "Practical Guidelines for Nutritional Support in Cancer Patients" (authors: Sytov A.V., Zuzov S.A., Leiderman I.N., Khoteev A.Zh. Malignant Tumors: Practical Guidelines RUSSCO #3s2, 2020 (vol. 10).43, https://rosoncoweb.ru/standarts/RUSSCO/2020/2020-43.pdf).

The principles of prevention and treatment of nephrotoxicity in breast cancer patients correspond tothe principles outlined in the guidelines "Practical Guidelines for the Correction of Nephrotoxicity of Antineoplastic Drugs" (authors: Gromova E.G., Biryukova L.S., Dzhumabaeva B.T., Kurmukov I.A. Malignant Tumors: Practical Guidelines RUSSCO #3s2, 2020 (vol. 10).46, https://rosoncoweb.ru/standarts/RUSSCO/2020/2020-46.pdf).

The principles of prevention and treatment of thromboembolic complications in breast cancer patients correspond to the principles outlined in the guidelines "Practical Guidelines for the Prevention and Treatment of Thromboembolic Complications in Cancer Patients" (authors: Somonova O.V., Antukh E.A., Dolgushin B.I., Elizarova A.L., Sakaeva D.D., Selchuk V.Yu., Tryakin A.A., Cherkasov V.A. Malignant Tumors: Practical Guidelines RUSSCO #3s2, 2020 (vol. 10).47, https://rosoncoweb.ru/standarts/RUSSCO/2020/2020-47.pdf).

The principles of prevention and treatment of the consequences of drug extravasation in breast cancer patients correspond to the principles outlined in the guidelines "Recommendations for the Management of Antineoplastic Drug Extravasation Consequences" (author: Buydenok Yu.V. Malignant Tumors: Practical Guidelines RUSSCO #3s2, 2020 (vol. 10).48, https://rosoncoweb.ru/standarts/RUSSCO/2020/2020-48.pdf).

The principles of prevention and treatment of immune-mediated adverse events in breast cancer patients correspond to the principles outlined in the guidelines "Practical Guidelines for the Management of Immune-Mediated Adverse Events" (authors: Protsenko S.A., Antimonik N.Yu., Bershtein L.M., Zhukova N.V., Novik A.V., Nosov D.A., Petenko N.N., Semenova A.I., Chubenko V.A., Kharkevich G.Yu., Yudin D.I. Malignant Tumors: Practical Guidelines RUSSCO #3s2, 2020 (vol. 10).50, https://rosoncoweb.ru/standarts/RUSSCO/2020/2020-50.pdf).

3.8. Nutritional therapy

To date, no reliable data have been obtained regarding the effect of dietary habits on the risk of developing breast cancer, or the risk of recurrence or progression of this disease in individuals with an already established diagnosis. There is evidence that a diet rich in fruits and vegetables, minimal sugar intake, and reduced alcohol consumption may be associated with a lower risk of developing breast cancer. In this regard, any changes in the patients' usual diet are not indicated unless dictated by the need to correct comorbid conditions, or to relieve or prevent complications of the ongoing treatment (surgical, medical, or radiation).

4. Medical Rehabilitation and Sanatorium-Resort Treatment

• psychoeducational interventions [244, 245];
• cognitive behavioral psychotherapy [246];

GCP BLoE 2Grade of Recommendation – B (Level of Evidence – 2).

• supportive psychotherapy [247].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• medical drainage massage of the upper limb in the postoperative period;
• early initiation of physical therapy exercises;
• weight control, prevention of obesity;
• prevention of erysipelas, skin care.

GCR CLEL 2Grade of Recommendation – C (Level of Evidence – 2).

• • anti-edema therapy, including manual lymphatic drainage;
  • wearing compression garments;
  • performing physical therapy exercises;
  • skin care [252];
  • intermittent pneumatic compression of the upper limb combined with complete decongestive therapy [253].

GCR CLEL 2Grade of Recommendation – C (Level of Evidence – 2).

• • low-frequency magnetotherapy combined with anti-edema therapy [258];

GCR CLEL 4Grade of Recommendation – C (Level of Evidence – 4).

5. Prevention and Dispensary Observation

• careful dynamic monitoring;
• surgical prevention (preventive mastectomy with immediate reconstruction and preventive salpingo-oophorectomy) [54, 93, 174].

GCR CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: the decision on performing prophylactic mastectomy and salpingo-oophorectomy must be made by a multidisciplinary team involving a medical geneticist, surgeon/plastic surgeon, oncologist, and medical psychologist; surgical prevention procedures for hereditary breast and ovarian cancer must be performed in a specialized oncological institution experienced in such interventions. If the patient refuses reconstruction after counseling by a medical psychologist, a simple mastectomy may be performed.

• examination 1 to 4 times a year (depending on the specific clinical situation) for the first 5 years, then annually [38, 54, 260];
• annual bilateral (in case of breast-conserving surgery) or contralateral mammography (by radiologists) combined with ultrasound of regional zones and the postoperative scar area (by ultrasound diagnostics physicians) [38, 54, 260].

GCR CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

Comments: any pathological conditions suspicious for endometrial cancer require timely diagnosis. Routine pelvic ultrasound and endometrial biopsy (diagnostic curettage) in the absence of symptoms are not recommended.

6. Organization of Medical Care

Medical care, with the exception of medical care within the framework of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation", is organized and provided:

1) in accordance with the regulations on the organization of medical care by types of medical care, approved by the authorized Federal Executive Authority;

2) in accordance with the procedure for the provision of medical care in the profile "oncology", mandatory for implementation throughout the Russian Federation by all medical organizations;

3) based on these clinical guidelines;

4) taking into account the standards of medical care approved by the authorized Federal Executive Authority.

Primary specialized health care is provided by an oncologist and other medical specialists at an outpatient oncological care center or in a primary oncological office, primary oncological department, or outpatient department of an oncological dispensary.

In case of suspicion or detection of an oncological disease in a patient, general practitioners, district general practitioners, general family physicians, medical specialists, and mid-level medical personnel shall refer the patient in the established manner for a consultation to an outpatient oncological care center or to a primary oncological office or primary oncological department of a medical organization to receive primary specialized medical care.

Consultation at an outpatient oncological care center or at a primary oncological office or primary oncological department of a medical organization must be conducted no later than 5 working days from the date of issuance of the referral for consultation. The oncologist of the outpatient oncological care center (in the absence of an outpatient oncological care center, the oncologist of the primary oncological office or primary oncological department) shall organize the collection of biopsy (surgical) material, as well as organize other diagnostic studies necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

If it is impossible to collect biopsy (surgical) material or perform other diagnostic tests at the medical organization that houses the outpatient oncological care center (primary oncological office, primary oncological department), the attending physician shall refer the patient to an oncological dispensary or a medical organization providing medical care to patients with oncological diseases.

The timeframe for pathomorphological studies required for the histological verification of malignant neoplasms of the oral cavity must not exceed 15 working days from the date of receipt of the biopsy (surgical) material by the pathomorphological bureau (department).

If an oncological disease is suspected and/or detected in a patient during the provision of emergency medical care, the patient is transferred or referred to medical organizations providing medical care to patients with oncological diseases to determine management tactics and the need for additional other methods of specialized antitumor treatment.

The oncologist of the outpatient oncological care center (primary oncological office, primary oncological department) shall refer the patient to an oncological dispensary or medical organizations providing medical care to patients with oncological diseases to clarify the diagnosis (if the oncologist of the outpatient oncological care center, primary oncological office, or primary oncological department is unable to establish the diagnosis, including the extent of the oncological process and the stage of the disease) and to receive specialized, including high-tech, medical care.

The time from the date of histological verification of a malignant neoplasm of the oral cavity—or from the date of establishing a preliminary diagnosis of a malignant neoplasm of the oral cavity (in the absence of medical indications for outpatient pathomorphological studies)—to the start of specialized (excluding high-tech) medical care for cancer patients in a medical organization providing care to cancer patients must not exceed 14 calendar days.

Specialized, including high-tech, medical care is provided by oncologists and radiation therapists in an oncological dispensary or in medical organizations providing medical care to patients with oncological diseases that hold a license, have the necessary material and technical base and certified specialists, in inpatient and day-hospital settings, and includes the prevention, diagnosis, and treatment of oncological diseases requiring the use of special methods and complex unique medical technologies, as well as medical rehabilitation.

In a medical organization providing medical care to patients with oncological diseases, the tactics of medical examination and treatment are established by a concilium of oncologists and radiation therapists, involving other medical specialists if necessary. The decision of the medical concilium is formalized in a protocol, signed by the participants of the medical concilium, and entered into the patient's medical documentation.

Indications for admission to an inpatient or day care unit of a medical organization providing specialized, including high-tech, medical care in the field of oncology are determined by a concilium of oncologists and radiation therapists, involving other medical specialists if necessary.

Indications for hospitalization in a medical organization in an emergency or urgent form are:

1) the presence of complications of the oncological disease requiring the provision of specialized medical care in an emergency and urgent form;

2) presence of complications of treatment (surgical intervention, RT, drug therapy, etc.) of the oncological disease.

Indications for hospitalization in a medical organization in a planned form are:

1) the need to perform complex interventional diagnostic medical procedures requiring subsequent monitoring in an inpatient or day-hospital setting;

2) the presence of indications for specialized antitumor treatment (surgical intervention, RT, including contact, EBRD and other types of RT, drug therapy, etc.) requiring monitoring in an inpatient or day hospital setting.

Indications for discharging a patient from a medical organization are:

1) completion of a course of treatment or one of the stages of providing specialized, including high-tech, medical care in an inpatient or day hospital setting, provided there are no treatment complications requiring drug correction and/or medical interventions in an inpatient setting;

2) refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day hospital setting established by the multidisciplinary team of the medical organization providing cancer care, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting;

3) in cases of non-compliance by the patient with prescriptions or the internal regulations of the medical and prophylactic institution, provided this does not threaten the patient's life and the health of others;

4) the need to transfer the patient to another medical organization according to the relevant medical specialty profile.

The conclusion on the advisability of transferring a patient to a specialized medical organization is made after a preliminary consultation on the provided medical documents and/or a preliminary examination of the patient by specialist physicians of the medical organization to which the transfer is planned.

7. Additional Information

There is no information in this section.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Zhukova, Lyudmila Grigorievna, Doctor of Medical Sciences, Deputy Director of the A.S. Loginov Moscow Clinical Scientific Center of the Moscow Healthcare Department, Moscow.
2. Andreeva, Yulia Yuryevna, Doctor of Medical Sciences, Professor at the Department of Pathological Anatomy, Russian Medical Academy of Continuous Professional Education (RMACPE), Moscow.
3. Zavalishina, Larisa Eduardovna, Doctor of Biological Sciences, Professor at the Department of Pathological Anatomy, RMACPE, Moscow.
4. Zakiryakhodzhaev, Aziz Dilshodovich, Doctor of Medical Sciences, Head of the Department of Breast and Skin Reconstructive and Plastic Oncology, P.A. Herzen Moscow Oncology Research Institute, Moscow.
5. Koroleva, Irina Albertovna, Doctor of Medical Sciences, Professor at the Department of Clinical Medicine of Postgraduate Education, Reaviz Medical University, Oncologist, Samara.
6. Nazarenko, Alexey Vitalievich, Candidate of Medical Sciences, Senior Researcher at the Department of General Oncology, A.S. Loginov Moscow Clinical Scientific Center of the Moscow Healthcare Department, Moscow.
7. Paltuev, Ruslan Malikovich, General Director of the All-Russian Public Organization "Russian Society of Oncomammologists", Senior Researcher at the Breast Tumor Department, N.N. Petrov National Medical Research Center of Oncology, Saint Petersburg.
8. Parokonnaya, Anastasia Anatolyevna, Doctor of Medical Sciences, Senior Researcher at the Radiosurgery Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Professor at the Department of Oncology and Radiology, Pirogov Russian National Research Medical University of the Russian Ministry of Health, Moscow.
9. Petrovsky, Alexander Valerievich, Candidate of Medical Sciences, Deputy Director for Regional Cancer Care Development, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Moscow.
10. Portnoy, Sergey Mikhailovich, Doctor of Medical Sciences, Frau Clinic LLC, Oncologist-Mammologist, Moscow.
11. Semiglazov, Vladimir Fedorovich, Academician of the Russian Academy of Natural Sciences, Corresponding Member of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Head of the Surgical Department, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Saint Petersburg.
12. Semiglazova, Tatyana Yuryevna, Doctor of Medical Sciences, Head of the Scientific Department of Innovative Methods of Therapeutic Oncology and Rehabilitation, N.N. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Professor at the Department of Oncology, Mechnikov North-Western State Medical University of the Russian Ministry of Health, Saint Petersburg.
13. Stenina, Marina Borisovna, Doctor of Medical Sciences, Leading Researcher at the Department of Clinical Pharmacology and Chemotherapy, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Moscow.
14. Stepanova, Alexandra Mikhailovna, Candidate of Medical Sciences, Chief Rehabilitation Specialist, "Vostanovlenie" Center for Diagnostics and Rehabilitation, Moscow.
15. Trofimova, Oksana Petrovna, Doctor of Medical Sciences, Leading Researcher at the Radiological Department of the Research Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Professor at the Department of Oncology, RMACPE of the Russian Ministry of Health, Moscow.
16. Tyulyandin, Sergey Alekseevich, Doctor of Medical Sciences, Professor, Head of the Department of Clinical Pharmacology and Chemotherapy, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Moscow.
17. Frank, Georgy Avraamovich, Academician of the Russian Academy of Sciences, Professor, Head of the Department of Pathological Anatomy, RMACPE, Moscow.
18. Frolova, Mona Alexandrovna, Candidate of Medical Sciences, Senior Researcher at the Department of Clinical Pharmacology and Chemotherapy, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Moscow.
19. Shatova, Yuliana Sergeevna, Doctor of Medical Sciences, Leading Researcher at the Department of Soft Tissue and Bone Tumors, Rostov Research Institute of Oncology.
20. Aleksey A. Nevolskikh, MD, DSc, Deputy Director for Clinical Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Moscow Region, Obninsk.
21. Ivanov Sergey Anatolyevich, Professor of the RAS, Doctor of Medical Sciences, Director of the A.F. Tsyb Medical Radiological Research Center, branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Moscow Oblast, Obninsk.
22. Zhanna V. Khaylova, MD, PhD, Deputy Director for Organizational and Methodological Work, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Moscow Region, Obninsk.
23. Gevorkyan Tigran Gagikovich, Deputy Director of the Research Institute of Clinical and Experimental Radiology, N.N. Blokhin National Medical Research Center of Oncology, Moscow.

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• oncologists;
• surgeons;
• radiotherapists;
• medical geneticists;
• medical students, residents, and postgraduate students.

Methods used for the collection/selection of evidence: searches in electronic databases, analysis of current scientific developments on the problem of breast cancer in the Russian Federation and abroad, generalization of the practical experience of Russian and foreign specialists.

Methods used for formulating recommendations – expert consensus.

Economic analysis: cost analysis was not performed, and pharmacoeconomic publications were not analyzed.

Method of recommendation validation:

• external expert review;
• internal expert review.

Description of the recommendation validation method

The preliminary version of these recommendations was reviewed by independent experts who were asked to comment on how comprehensible the interpretation of the evidence underlying the recommendations is.

Comments were received from primary care oncologists regarding the clarity of the presentation of the recommendations and their assessment of the importance of the recommendations as a working tool in daily practice.

The comments received from experts were carefully systematized and discussed by the chairman and members of the working group. Each point was discussed, and changes made to the recommendations were recorded. If no changes were made, the reasons for refusing to make changes were recorded.

Consultations and expert review

The draft guidelines were also reviewed by independent experts, who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

For the final editing and quality control, the guidelines were re-analyzed by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account, and the risk of systematic bias in the development of the guidelines was minimized.

Procedure for updating clinical guidelines

Updating is carried out at least once every 3 years and not more often than once every 6 months, taking into account new information that has emerged on the diagnosis and management of patients suffering from breast cancer. The decision to update is made by the Russian Ministry of Health based on proposals submitted by medical professional non-profit organizations. The formulated proposals must take into account the results of a comprehensive assessment of medicines, medical devices, and the results of clinical approbation.

When selecting publications as potential sources of evidence, the methodology used in each study is examined to verify its reliability. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations derived from it.

Grading system for levels of evidence for diagnostic methods (diagnostic interventions)

Grading system for levels of evidence for prevention, treatment and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)

Grades of Recommendation Scale for Prevention, Diagnostic, Treatment, and Rehabilitation Methods (Preventive, Diagnostic, Therapeutic, Rehabilitation Interventions)

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

1. Order of the Russian Ministry of Health No. 915n dated November 15, 2012, "On approval of the Procedure for the provision of medical care to the population in the profile 'Oncology'."
2. Order of the Russian Ministry of Health No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care".
3. Order of the Russian Ministry of Health No. 782n dated November 9, 2012, "On approval of the standard of specialized medical care for stage IIIB, C malignant neoplasms of the breast (surgical treatment)."
4. Order of the Ministry of Health of the Russian Federation No. 612n dated November 7, 2012, "On approval of the standard of specialized medical care for primary generalized and recurrent forms of stage IV malignant neoplasms of the breast - primary; stages I - IV - progression (systemic medical, including chemotherapeutic, treatment)."
5. Rdf. Decree No. 2738-r dated December 10, 2018 "On approval of the list of vital and essential medicines for 2019, as well as lists of medicines for medical use and the minimum assortment of medicines necessary for the provision of medical care."
6. Order of the Russian Ministry of Health No. 103n dated February 28, 2019, "On approval of the procedure and timeframe for the development of clinical guidelines, their revision, the standard form of clinical guidelines, and the requirements for their structure, composition, and scientific validity of the information included in the clinical guidelines" (registered with the Russian Ministry of Justice on May 8, 2019, No. 54588).

Current instructions for medicinal products mentioned in these clinical guidelines can be found on the website http://grls.rosminzdrav.ru.

Appendix B. Physician Action Algorithms

Fig. 1. Flowchart for the diagnosis and treatment of a breast cancer patient

Fig. 2. Recommended algorithm of diagnostic and treatment measures depending on the clinical group of breast cancer

Notes:

¹neoadjuvant drug therapy for stage I is recommended only within clinical trials. Neoadjuvant chemotherapy is recommended to be carried out using standard regimens (see Tables 4, 5) and mandatory compliance with the recommended dose intensity (standard doses and intervals between cycles). In the absence of necessary material resources guaranteeing the delivery of the recommended neoadjuvant drug therapy (anthracyclines and related compounds, taxanes, trastuzumab**, pertuzumab**, #G-CSF**), for primarily operable breast cancer, surgical treatment is recommended at the first stage;

²adjuvant chemotherapy is not recommended for patients who have received a full course of neoadjuvant chemotherapy. In cases where neoadjuvant chemotherapy was not fully completed before surgery for any reason, administering the missing cycles in the postoperative period is recommended. For breast cancer patients with a triple-negative phenotype (negative ER, PR, and HER2) who received a full course of neoadjuvant chemotherapy with anthracyclines and related compounds and taxanes, in the presence of invasive residual tumor corresponding to RCB II–III or, if RCB assessment is not feasible, in the presence of residual tumor in regional lymph nodes (regardless of the degree of pathomorphosis in the primary breast tumor) or residual tumor in the breast corresponding to Lavnikova grade 0–II drug pathomorphosis (regardless of the state of regional lymph nodes), adjuvant chemotherapy with #capecitabine** (2000 mg/m² on days 1–14 every 3 weeks for 6 months) may be prescribed [108];

³For patients with HER2-positive breast cancer who received neoadjuvant drug therapy with anthracyclines and related compounds and/or taxanes in combination with trastuzumab** (± pertuzumab**), in the presence of an invasive residual tumor corresponding to RCB class II–III, or if RCB assessment is not feasible, with residual tumor in regional lymph nodes (regardless of the degree of pathomorphosis in the primary breast tumor) or with residual tumor in the breast corresponding to Lavnikova drug pathomorphosis grade 0–II (regardless of the status of regional lymph nodes), trastuzumab emtansine** may be prescribed as adjuvant therapy at 3.6 mg/kg IV on day 1 every 3 weeks, for up to 14 cycles [114].

Fig. 3. Recommended sequence of various adjuvant therapy modalities

Fig. 4. Recommended treatment tactics for primarily operable breast cancer (T2N0M0, T2N1M0, T3N0M0, T3N1M0) in the case of neoadjuvant drug therapy

Notes:

¹adjuvant CT is not recommended for patients who received full neoadjuvant CT; in individual cases where preoperative CT was for any reason not fully completed, missing cycles are recommended in the postoperative period. For patients with triple-negative breast cancer (negative ER, PR, and HER2) who received full neoadjuvant CT with anthracyclines and related compounds and taxanes, in the presence of invasive residual tumor corresponding to RCB II–III or, if RCB assessment is not feasible, with residual tumor in regional lymph nodes (regardless of the degree of pathomorphosis in the primary breast tumor) or with residual tumor in the breast corresponding to grade 0–II drug pathomorphosis according to Lavnikova (regardless of regional lymph node status), adjuvant CT with #capecitabine** (2000 mg/m² on days 1–14 every 3 weeks for 6 months) may be prescribed [108];

²patients with HER2-positive breast cancer who received neoadjuvant drug therapy with anthracyclines and related compounds and/or taxanes combined with trastuzumab** (± pertuzumab**), in the presence of invasive residual tumor corresponding to RCB II–III or, if RCB assessment is not feasible, in the presence of residual tumor in regional lymph nodes (regardless of the degree of pathomorphosis in the primary breast tumor) or residual tumor in the breast corresponding to Lavnikova grade 0–II drug pathomorphosis (regardless of the state of regional lymph nodes), #trastuzumab emtansine** 3.6 mg/kg IV on day 1 once every 3 weeks, for up to 14 cycles may be prescribed as adjuvant therapy [114];

³pathomorphological examination should include evaluation of the grade of pathomorphological response;

⁴IHC examination of the residual tumor is desirable, with adjustment of adjuvant therapy if necessary.

Fig. 5. Recommended sequence of different treatment modalities in neoadjuvant therapy

Fig. 6. Recommended treatment tactics for locally advanced primarily inoperable breast cancer (T0N2M0, T1N2M0, T2N2M0, T3N2M0, T4N0-2M0, T1-4N3M0)

Notes:

¹neoadjuvant endocrine therapy may be recommended for postmenopausal patients with luminal A breast cancer subtype;

²adjuvant CT is not recommended for patients who received a full course of neoadjuvant CT. In certain cases, when preoperatively CT was for any reason not fully completed, completing the remaining cycles in the postoperative period is recommended. Breast cancer patients with triple-negative phenotype (negative ER, PR, and HER2) who received a full course of neoadjuvant CT with anthracyclines, related compounds, and taxanes, in the presence of an invasive residual tumor corresponding to RCB-II–III or, if RCB assessment is not feasible, with residual tumor in regional lymph nodes (regardless of the degree of pathomorphosis in the primary breast tumor) or with residual tumor in the breast corresponding to grade 0–II drug pathomorphosis according to Lavnikova (regardless of regional lymph node status), may be prescribed adjuvant CT with #capecitabine** (2000 mg/m² on days 1–14 every 3 weeks for 6 months) [108];

³for patients with HER2-positive breast cancer who received neoadjuvant medical therapy with anthracyclines and related compounds and/or taxanes combined with trastuzumab** (± pertuzumab**), in the presence of an invasive residual tumor corresponding to RCB II–III or, if RCB evaluation is not feasible, with a residual tumor in regional lymph nodes (regardless of the degree of pathomorphosis in the primary breast tumor) or with a residual tumor in the breast corresponding to grade 0-II drug pathomorphosis according to Lavnikova (regardless of the status of regional lymph nodes), adjuvant therapy with trastuzumab emtansine** 3.6 mg/kg IV on day 1 every 3 weeks, up to 14 cycles, may be prescribed [114];

⁴pathological examination should include assessment of the grade of pathological response;

⁵IHC examination of the residual tumor with adjustment of adjuvant therapy if necessary is recommended;

⁶surgical treatment is not indicated if an operable state is not achieved as a result of medical and radiation therapy, except in cases where surgical treatment can improve quality of life.

Fig. 7. Algorithm for selecting therapy for luminal breast cancer in postmenopausal patients and women of reproductive age receiving ovarian suppression, depending on prior treatment and its efficacy

Notes:

¹ ≤12 months after completion of adjuvant endocrine therapy; ² ≥12 months after completion of adjuvant endocrine therapy; ³ endocrine therapy regimen depends on prior treatment and its efficacy.

Fig. 8. Recommended medical therapy algorithm for metastatic hormone-dependent breast cancer

Appendix C. Patient Information

Recommendations for chemotherapy complications: contact your oncologist; if unable to contact an oncologist, consult a general practitioner:

• if body temperature is ≥38 °C:

• • consult an oncologist/general practitioner,
  • monitor temperature every 3 hours;

• for stomatitis:

• • diet: mechanically, chemically, and thermally sparing food,
  • consult an oncologist;

• for diarrhea:

• • diet: exclude fatty, fried, spicy, smoked, sweet, dairy, and high-fiber foods; lean meats, flour products, fermented dairy products, and rice water are allowed,
  • adequate fluid intake,
  • consult an oncologist/general practitioner;

• for nausea:

• • consult an oncologist/general practitioner.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Lymphedema grade and stage scoring scale

Depending on the stages of complication development, the following stages of secondary lymphedema have been proposed in Russia: transient (stage I), soft (stage II), firm (stage III), and deforming (stage IV) edema [180, 181].

The International Society of Lymphology (ISL) [145] has defined 4 severity grades and 3 clinical stages of lymphedema.

Lymphedema grades

Grade 1: difference in circumference or volume between the healthy and affected limb is 5–10%. There is a change in the normal contour and architectonics of the limb (compared to the healthy limb). Edema is characterized by pitting on pressure. Edema decreases with limb elevation or by wearing compression garments. The arm is slightly dense and resilient.

Grade 2: difference between the healthy and affected limb is 10–30%. Significant noticeable change in shape, disappearance of skinfolds. Edema is firmer and more resilient, skin is taut.

Grade 3: difference between the healthy and affected limb is more than 30%; the arm is deformed, its function is impaired. Lymphorrhea through skin defects may occur. Edema is firm and resilient. Skin is taut and shiny.

Grade 4: the arm is "afunctional". Formation of lymphangiosarcoma is possible.

Lymphedema stages

Stage 0 (subclinical, latent stage): characterized by the absence of visible edema, absence of pitting on pressure, and a sensation of heaviness or local swelling (may persist for months or years before visible edema appears).

Stage I (mild stage): visible edema. Pitting may or may not form.

Stage II (moderate stage): visible edema with pitting. Skin is indurated, thinned.

Stage III (severe stage): visible tissue edema, significant enlargement and change in limb shape. Skin and underlying tissues are indurated, thickened, and no pitting occurs. Lymphorrhea through skin defects is possible.

The grade of lymphedema according to ISL recommendations is assessed by the difference in limb circumferences.

Depending on the difference in limb circumferences, a classification has been proposed in Russia, distinguishing the following grades of edema [180, 181]:

I – increase in affected limb circumference up to 1–2 cm

II – from 2 to 6 cm

III – from 6 to 10 cm

IV – more than 10 cm

Appendix G2. Assessment of tumor pathological response grade to prior therapy (RCB system)

Russian title: Assessment of tumor pathological response grade to prior therapy (RCB system).

Original title (if any): Residual cancer burden.

Source (official developer website, validation publication): Symmans W. F. et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy // Journal of Clinical Oncology. – 2007. – Vol. 25. – No. 28. – P. 4414–4422.

Type: index.

Purpose: assessment of the tumor pathological response grade to prior therapy.

Content (template):

The RCB system is a mathematical model proposed by W.F. Symmans et al. in 2007 based on the assessment of certain residual tumor characteristics and patient recurrence-free survival curves. Based on their study, the authors proposed the formula:

RCB = 1,4 (f_invd_prim)^0,17 + [4 (1 – 0,75^LN) d_met]^0,17,

where d_prim = âd1d2, where d1, d2 are microscopic dimensions of the tumor bed;

f_inv = (1 – (%CIS/100)) (%CA/100) is the extent of the invasive component calculated from the percentage of carcinoma in situ (CIS) and invasive carcinoma (CA) in the tumor;

LN is the number of lymph nodes with metastases,

dmet is the largest diameter of the metastasis in the lymph node.

Key (interpretation):

The calculation result is the residual tumor class (residual cancer burden), ranked from 0 to III:

• RCB–0 (pCR, pathological complete response) – index value of 0;
• RCB–I (minimal residual disease) – index value <1.36, low risk of disease progression;
• RCB–II (moderate residual disease) – index value 1.36–3.28, intermediate risk of disease progression;
• RCB–III (extensive residual disease) – index value >3.28, high risk of disease progression.

To calculate the RCB index, a free online calculator available on the website can be used

http://www.mdanderson.org/education-and-research/resources-for-professionals/clinical-tools-and-resources/clinical-calculators/calculators-cellularity-guide.pdf.