BREAST CANCER

- Acknowledgement

▪️ We would like to acknowledge the Oncology Committee of Egyptian health council (EHC) Guidelines and Breast Cancer Scientific Committee, for adapting this Guidelines.

▪️ Chair of the Committee of Egyptian health council Guidelines: Prof Hussein Khaled.

▪️ The Oncology Committee Members: Ebtesam Saad Eldin, Ehab Khalil, Emad Hamada, Fouad Abuotaleb, Hesham Elghazaly, Hesham Tawfik, Khaled Abdelkarim, Lobna ezz Elarab, Mary Gamal, Mohamed Abdel Mooti, Mohamed Gamil, Nervana Hussein, Ola Khorshid, Omar Sherif Omar, Rasha Fahmi, Rasha Shaltout, Samir Shehata, Yousri Wasef & Yousri Rostom.

▪️ The Breast Cancer Scientific Committee Members: Mohamed Gamil, Lobna Ezz Elarab, Hesham Elghazaly, Ehab Khalil, Rasha Fahmi, Rasha Shaltout, Omar Sherif Omar.

- Abbreviations

AI           Aromatase inhibitor

AJCC      American joint committee on cancer

Ax          Axilla 

BC         Breast cancer 

BCT        Breast conserving therapy 

BCS        Breast conserving surgery 

Bx          Biopsy

CEM      Contrast-enhanced mammography 

CT          Chemotherapy

EBC        Early breast cancer

ECOG     The Eastern Cooperative Oncology Group

ESMO    European society for medical oncology

ET          Endocrine therapy 

ER          Estrogen receptors 

FH           Family history 

G             Gauge

H&E        Hematoxylin and eosin 

HER2      Human epidermal growth factor receptor2

HR           Hormone receptors 

IBC          Inflammatory BC 

IBTR        Ipsilateral breast tumor recurrence

IHC          Immunohistochemistry

IKWG       International Ki67 in Breast Cancer Working Group

IM           Internal mammary 

ISH          In-situ hybridization

LABC       Locally advanced breast cancer

LN           Lymph nodes 

MDT       Multi-disciplinary team

Mets       Metastasis 

MRI         Magnetic resonance imaging

MRM      Modified radical mastectomy. 

NACT      Neoadjuvant chemotherapy

NCCN      National comprehensive cancer network

NMBC     Non metastatic breast cancer

NSM        Nipple-sparing mastectomy

OFS         Ovarian function suppression

pCR         Pathological complete response

PgR         Progesterone receptor

PO           Per oral

PST          Primary systemic therapy

RT            Radiotherapy 

SC            Supraclavicular  

SLNB       Sentinel LN biopsy 

SNM         Sono-mammography 

SSM          Skin-sparing mastectomy 

TN             Triple negative

TCH          Taxotere carboplatin Herceptin

U/S           Ultrasound

WLE         Wide local excision.

- Glossary

Non-Metastatic Breast Cancer:

Includes patients who have Early Breast Cancer (EBC) and Locally advanced Breast Cancer (LABC).

➡️  EBC: This includes ductal carcinoma in situ and stage I, stage IIA, stage IIB, and stage IIIA breast cancers.

➡️  LABC: this includes   inoperable breast adenocarcinoma without distant metastases stage  IIIB, and C.

Menopausal status (Defined by NCCN)

Postmenopausal status:

Premenopausal status:

Perimenopausal status:

Definitions of molecular subtypes of breast cancer according to: (The ESMO Clinical Practice Guidelines, 2023):

➡️  Luminal A : (ER-positive, HER2-negative, Ki67 low, PgR high)         

➡️  Luminal B : 

➡️ HER2 overexpression (nonluminal): (HER2-positive, ER and PgR absent)

➡️ Triple-negative: (ER and PgR absent, HER2-negative)

- Executive Summary

This guidance provides an evidence-based approach to the diagnosis, staging, treatment and follow up of patients diagnosed with non-metastatic breast cancer (NMBC).

- Introduction

Breast cancer is the most common cancer in females and the second most common in the Egyptian population with more than 26 thousand newly diagnosed cases. ⁽¹⁾ Moreover, it is also the second cause of cancer death in Egypt after hepatocellular carcinoma with estimated mortality rate around 10% in 2022. Approximately 46,000 incident cases are forecasted in 2050.

➡️ Purpose and scope

These guidelines will help to improve the quality of care for non-metastatic breast cancer patients via providing a uniform standard of care across the country to help in early diagnosis and treatment for breast cancer, with less aggressive treatment options and improved clinical outcomes. These guidelines cover  primary diagnosis, staging, treatment and follow-up of breast cancer patients.

➡️ Target audience

Clinicians who are involved in the care and treatment of patients with breast cancer, including medical oncologists, radiation oncologists, clinical oncologists , surgeons, interventional radiologists, radiologists and pathologists.

- Methodology

A comprehensive search for guidelines was undertaken to identify the most relevant guidelines to consider for adaptation.   inclusion/exclusion criteria followed in the search and retrieval of guidelines to be adapted: 

 All retrieved Guidelines were screened and appraised using AGREE II instrument (www.agreetrust.org) by at least two members. the panel decided a cutoff point or rank the guidelines (any guideline scoring above 50% on the rigor dimension was retained) 

The NCCN, ESMO, NICE guidelines are the main sources used while formulating the national guidelines for breast cancer.

- Evidence assessment

According to WHO handbook for Guidelines we used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach to assess the quality of a body of evidence, develop and report recommendations. GRADE methods are used by WHO because these represent internationally agreed standards for making transparent recommendations. Detailed information on GRADE is available through the on the following sites: 

Table 1: Quality of evidence in GRADE

Table 2: Significance of the four levels of evidence 

Table 3: Factors that determine how to upgrade or downgrade the quality of evidence.

- The strength of the recommendation

The strength of a recommendation communicates the importance of adherence to the recommendation: 

➡️Strong recommendations: With strong recommendations, the guideline communicates the message that the desirable effects of adherence to the recommendation outweigh the undesirable effects. This means that in most situations the recommendation can be adopted as policy. 

➡️Conditional recommendations: These are made when there is greater uncertainty about the four factors above (Table 2) or if local adaptation must account for a greater variety in values and preferences, or when resource use makes the intervention suitable for some, but not for other locations. This means that there is a need for substantial debate and involvement of stakeholders before this recommendation can be adopted as policy. 

When not to make recommendations; when there is lack of evidence on the effectiveness of an intervention, it may be appropriate not to make a recommendation.

- Recommendations

1. Workup for Newly Diagnosed Breast Cancer:

Strong recommendation, Moderate quality level of evidence, Narrative Review ⁽²⁾.

Strong recommendation, Moderate quality level of evidence, Narrative Review (2).

Strong recommendation, high quality level of evidence, Systemic review ⁽³⁾.

Strong recommendation, high quality level of evidence meta-analysis ⁽⁴⁾.

Strong recommendation, high quality level of evidence, Systemic Review ⁽⁵⁾.

Strong recommendation, Moderate quality level of evidence, Narrative Review ^(6,7).

Conditional recommendation, Moderate quality level of evidence, Narrative Review (6,7).

Strong recommendation, high quality level of evidence, Meta analysis ^{(8, 9)}.

Strong recommendation, high quality level of evidence, Systemic Review ^{(10, 11, 12)}.

Strong recommendation, high quality level of evidence, Randomized Trial ⁽¹³⁾.

2.     DCIS

Strong recommendation, high quality level of evidence, Randomized Trial ⁽¹⁴⁾

Strong recommendation, high quality level of evidence, Randomized Trial ^(15,16)

Conditional, Small, randomized trials or meta-analyses with demonstrated heterogeneity ⁽¹⁷⁾

3. Surgery

Strong recommendation, high quality level of evidence, Randomized Trial ⁽¹⁸⁾

 Strong recommendation, high quality level of evidence, Randomized Trial ⁽¹⁸⁾

Conditional recommendation, high quality level of evidence, Randomized Trial ⁽¹⁹⁾

Strong recommendation, high quality level of evidence, Randomized Trial ⁽²⁰⁾

Strong recommendation, high quality level of evidence, Randomized Trial ⁽²¹⁾

Strong recommendation, high quality level of evidence, Randomized Trial ^(22,23)

Strong recommendation, high quality level of evidence, Randomized Trial ^(24,25)

4. Radiotherapy

Strong recommendation, high quality level of evidence, Randomized Trial ⁽²⁶⁾

Strong recommendation, high quality level of evidence, Randomized Trial ^(27,28)

Conditional recommendation, high quality level of evidence, Randomized Trial ^(27,28)

Strong recommendation, high quality level of evidence, Randomized Trial ⁽²⁹⁾

Strong recommendation, high quality level of evidence, Randomized Trial ⁽²⁹⁾

5.  Adjuvant Systemic Therapy:

Adjuvant Endocrine Treatment.

Strong recommendation, high quality level of evidence, Randomized Trial ^(30,31)

(In Adjuvant Endocrine Treatment (Luminal A and B), Premenopausal):

Strong recommendation, high quality level of evidence, Phase III Randomized Trial ⁽³⁰⁾.

Strong recommendation, high quality level of evidence, Phase III Randomized Trial ⁽³¹⁾

Strong recommendation, high quality level of evidence, Meta-analysis ⁽³²⁾

(Adjuvant Endocrine Treatment (Luminal A and B), Postmenopausal):

Strong recommendation, high quality level of evidence, Meta-analysis ⁽³³⁾.

Strong recommendation, high quality level of evidence, Systemic Review. ^(33,34)

Adjuvant Chemotherapy:

(Adjuvant chemotherapy in Triple negative, High risk Luminal B, HER2-negative):

Strong recommendation, high quality level of evidence ⁽³⁵⁾.

Strong recommendation, high quality level of evidence ⁽³⁵⁾.

(Adjuvant setting in Her-2 positive, High risk Luminal B HER2-postive):

Strong recommendation, high quality level of evidence, Meta-analysis.^{(39, 40, 41)}.

Conditional Moderate Quality level of evidence, Randomized Phase III ,Non-inferiority Trial. ⁽⁴²⁾

Strong recommendation, high quality level of evidence, meta-analysis ^{(40, 41)}.

Conditional Moderate Quality level of evidence, Randomized Trial. ⁽⁴³⁾

Strong recommendation, high quality level of evidence, Randomized Trial. ^(58,59).

(All intrinsic subtypes):

Strong recommendation, high quality level of evidence, Systemic Review /Prospective trial ^(47-49).

Strong recommendation, high quality level of evidence, Meta-analysis ^(49,50)

(HER2 positive subtype):

Conditional High-Quality level of evidence, Randomized Trial ⁽⁴⁵⁾

(Luminal A like subtype special situations):

Conditional Moderate Quality level of evidence, Systemic Review ⁽⁵³⁾

(TNBC subtype):

Conditional recommendation Moderate Quality level of evidence, Randomized Trial ^{(51, 52)}

(Post neoadjuvant therapy):

Strong recommendation, high quality level of evidence, Randomized Trial. ⁽⁴⁴⁾.

Strong  recommendation, High Quality level of evidence, Randomized Trial. ^(43,45)

Strong recommendation High Quality level of evidence, Randomized Trial. ⁽⁴⁶⁾

6. Surveillance:

Strong recommendation, Moderate quality level of evidence, Systemic Review ⁽⁵⁵⁾.

Strong Recommendations, Moderate level of Evidence, Systemic Review ⁽⁵⁶⁾.

➡️ Research Gaps 

•  Head-to-Head comparison for adjuvant Olaparib versus Capecitabine in TNBC received neoadjuvant treatment with residual disease.

• Pembrolizumab neoadjuvant exclusively versus neoadjuvant and adjuvant regarding survival benefit, toxicity including financial toxicity and quality of life.

Update of this guideline 

• This guideline will be updated whenever there is new evidence.

- Annexes

 Breast cancer staging:

➡️American Joint Committee on Cancer (AJCC) TNM Staging System 8^th edition 2017: ⁽⁶⁰⁾

 Primary Tumor (T) The T category of the primary tumor is defined by the same criteria regardless of whether it is based on clinical or pathological criteria, or both. The T category is based primarily on the size of the invasive component of the cancer. The maximum size of a tumor focus is used as an estimate of disease volume. The largest contiguous dimension of a tumor focus is used, and small satellite foci of noncontiguous tumor are not added to the size. The cellular fibrous reaction to invasive tumor cells is generally included in the measurement of a tumor prior to treatment; however, the dense fibrosis observed following neoadjuvant treatment is generally not included in the pathological measurement because its extent may overestimate the residual tumor volume. The clinical size of a primary tumor (T) can be measured based on clinical findings (physical examination and imaging modalities, such as mammography, ultrasound, and MR imaging) and pathological findings (gross and microscopic measurements). Clinical tumor size (cT) should be based on the clinical findings that are judged to be most accurate for a particular case, although it may still be somewhat inaccurate because the intent of some breast cancers is not always apparent with current imaging techniques and because tumors are composed of varying proportions of noninvasive and invasive disease, which these techniques are currently unable to distinguish. Size should be measured to the nearest millimeter. If the tumor size is slightly less than or greater than a cutoff for a given T classification the size should be rounded to the millimeter reading that is closest to the cutoff. For example, a reported size of 4.9 mm is reported as 5 mm, or a size of 2.04 cm is reported as 2.0 cm (20 mm). The exception to this rounding rule is for a breast tumor sized between 1.0 and 1.4 mm. These sizes are rounded up to 2 mm, because rounding down would result in the cancer’s being categorized as microinvasive carcinoma (T1mi) defined as a size of 1.0 mm or less.

➡️Definitions for T, N, M

TX Primary tumor cannot be assessed.

T0 No evidence of primary tumor

Tis (DCIS)* Ductal carcinoma in situ Tis (Paget) Paget disease of the nipple NOT associated with invasive carcinoma and/or carcinoma in situ (DCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized based on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still be noted.

T1 Tumor ≤20 mm in greatest dimension

T1mi Tumor ≤1 mm in greatest dimension

T1a Tumor >1 mm but ≤5 mm in greatest dimension (round any measurement >1.0–1.9 mm to 2 mm) T1b Tumor >5 mm but ≤10 mm in greatest dimension

T1c 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 and/ or to the skin (ulceration or macroscopic nodules); invasion of the dermis alone does not qualify as T4

T4a Extension to the chest wall; invasion or adherence to pectoralis muscle in the absence of invasion of chest wall structures does not qualify as T4

T4b Ulceration and/or ipsilateral macroscopic satellite nodules and/or edema (including peau d’orange) of the skin that does not meet the criteria for inflammatory carcinoma

T4c Both T4a and T4b are present

T4d Inflammatory carcinoma

*Note: Lobular carcinoma in situ (LCIS) is a benign entity and is removed from TNM staging in the AJCC Cancer Staging Manual, 8th Edition

➡️Regional Lymph Nodes (N) Clinical (cN)

 cNX* Regional lymph nodes cannot be assessed (e.g., previously removed)

cN0 No regional lymph node metastases (by imaging or clinical examination)

cN1 Metastases to movable ipsilateral level I, II axillary lymph node(s)

cN1mi** Micro metastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)

cN2 Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted: or in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases.

cN2a Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures.

cN2b Metastases only in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases

cN3 Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement; or in ipsilateral internal mammary lymph node(s) with level I, II axillary lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement

cN3a Metastases in ipsilateral infraclavicular lymph node(s)

cN3b Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)

cN3c Metastases in ipsilateral supraclavicular lymph node(s)

Note: (sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or fine needle aspiration/core needle biopsy respectively.

*The cNX category is used sparingly in cases where regional lymph nodes have previously been surgically removed or where there is no documentation of physical examination of the axilla.

**cN1mi is rarely used but may be appropriate in cases where sentinel node biopsy is performed before tumor resection, most likely to occur in cases treated with neoadjuvant therapy.

➡️Pathologic (pN)

pNX regional lymph nodes cannot be assessed (e.g., not removed for pathological study or previously removed)

pN0 No regional lymph node metastasis identified or ITCs only

pN0(i+) ITCs only (malignant cells clusters no larger than 0.2 mm) in regional lymph node(s)

pN0(mol+) Positive molecular findings by reverse transcriptase polymerase chain reaction (RT-PCR); no ITCs detected.

pN1 Micrometastases; or metastases in 1–3 axillary lymph nodes; and/or in clinically negative internal mammary nodes with micrometastases or macrometastases by sentinel lymph node biopsy

pN1mi Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger than 2.0 mm)

pN1a Metastases in 1–3 axillary lymph nodes, at least one metastasis larger than 2.0 mm

pN1b Metastases in ipsilateral internal mammary sentinel nodes, excluding ITCs pN1c pN1a and pN1b combined.

pN2 Metastases in 4–9 axillary lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the absence of axillary lymph node metastases

pN2a Metastases in 4–9 axillary lymph nodes (at least one tumor deposit larger than 2.0 mm)

pN2b Metastases in clinically detected internal mammary lymph nodes with or without microscopic confirmation; with pathologically negative axillary nodes

pN3 Metastases in 10 or more axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes; or positive ipsilateral internal mammary lymph nodes by imaging in the presence of one or more positive level I, II axillary lymph nodes; or in more than three axillary lymph nodes and micro metastases or macro metastases by sentinel lymph node biopsy in clinically negative ipsilateral internal mammary lymph nodes; or in ipsilateral supraclavicular lymph nodes

pN3a Metastases in 10 or more axillary lymph nodes (at least one tumor deposit larger than 2.0 mm); or metastases to the infraclavicular (level III axillary lymph) nodes

pN3b pN1a or pN2a in the presence of cN2b (positive internal mammary nodes by imaging); or pN2a in the presence of pN1b

pN3c Metastases in ipsilateral supraclavicular lymph nodes

Note: (sn) and (f) suffixes should be added to the N category to denote confirmation of metastasis by sentinel node biopsy or FNA/core needle biopsy respectively, with NO further resection of nodes

➡️Distant Metastasis (M)

M0 No clinical or radiographic evidence of distant metastases*

cM0(i+) No clinical or radiographic evidence of distant metastases in the presence of tumor cells or deposits no larger than 0.2 mm detected microscopically or by molecular techniques in circulating blood, bone marrow, or other nonregional nodal tissue in a patient without symptoms or signs of metastases

cM1 Distant metastases detected by clinical and radiographic means

pM1 Any histologically proven metastases in distant organs; or if in non-regional nodes, metastases greater than 0.2 mm

 AJCC Anatomic Stage Groups

- References