GUDELINE

Ghid de diagnostic şi tratament în cancerul sânului

 Guide to diagnosis and treatment of breast cancer

First published: 28 octombrie 2020

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/OnHe.52.3.2020.3709

Abstract

The guide is addressed to medical oncologists who, ac­cor­ding to the European Society of Medical Oncology (ESMO), are “cancer specialists” who follow the patient and the tra­jec­tory of his disease from diagnosis to the end of his life. Like any guide, it cannot cover all situations that arise in practice. Therefore, it does not replace the case analysis per­formed in the tumor board or in the clinical sections. The guide brings together evidence-based guidance re­com­mended by ASCO and ESMO. Medicines that have not yet been reimbursed in Romania are reported. The re­com­mendation is that, in order to establish the the­ra­peu­tic plan of a patient, the protocol of the National Health Insurance House should be consulted in order to reconcile the theoretical therapeutic possibilities with those possible in our country.

Keywords
breast cancer, diagnosis, treatment, guideline

Rezumat

Ghidul se adresează medicilor oncologi care, în concepţia Societăţii Europene de Oncologie Medicală (ESMO), sunt „specialiştii în cancer” care urmăresc pa­cien­tul şi traiectoria bolii sale de la diagnostic până la sfâr­şi­tul vieţii aces­­tuia. Ca orice ghid, nu poate acoperi toate si­tua­ţiile care apar în practică. De aceea, nu în­lo­cuieşte analiza cazului efec­tua­tă în tumor board sau pe secţiile clinice. Ghidul reuneşte in­di­­ca­­ţiile bazate pe do­vezi, recomandate de ASCO şi ESMO. Sunt semnalate me­di­ca­mentele care nu au încă rambursare în România. Re­co­man­darea este ca, pentru stabilirea pla­nu­lui te­ra­peu­tic al unui pacient, să se consulte şi protocolul Casei Na­ţio­nale de Asigurări de Sănătate, pentru a pune în acord po­si­bilităţile terapeutice teoretice cu cele posibile în ţara noastră. 

1. Epidemiology and etiology of breast cancer

a) Distribution: worldwide – 1.4 million cases per year; in Europe – 450,000 per year

  • the incidence is higher in Western Europe, North America, Australia and New Zealand;

  • the incidence is lower in Asia and Africa;

  • the highest cause of mortality in women: >450,000 worldwide; >139,000 in Europe;

  • it occurs 100 times more frequently in women than in men(1).

b) Genetic predisposition: approximately 10% of cases

  • BRCA-1 germline;

  • BRCA-2 germline;

  • Li-Fraumeni syndrome;

  • other gene mutations: PTEN, CHECK 2, RAD-51, PALB2(2).

c) Etiological factors: exposure to endogenous estro­gens, nulliparity

  • first pregnancy after 30 years old (it increases the risk of cancer 2-5 times compared to first pregnancy <18 years old);

  • premature menarche <12 ani old;

  • late menopause >55 years old;

  • lactation can reduce the risk of cancer;

  • postmenopausal hormone replacement therapy: it increases the risk of breast cancer in women with intact uterus by 24%.

d) Benign lesions, which increase the risk: proliferative lesions with atypia increase by 20% the risk in pacients with a familiar history of breast cancer; LCIS: in one study, 15% of patients developed invasive carcinoma in the ipsilateral breast, 9.3% in the opposite side breast, at a follow-up of 10 years;

  • papillomas;

  • sclerosis adenosis.

e) Physical inactivity: obesity increases the risk of breast cancer after menopause, while physical activity, even moderate, lowers the risk of breast cancer.

f) Ionizing radiation: thoracic radiotherapy increases the risk of breast cancer (the effects are seen decades after exposure)

g) Ethanol + tobacco: active smoking before a full-term pregnancy is particularly dangerous.

h) Increased breast density(3).

2. Histopathological classification

  • Ductal carcinoma (70-80% of cases) is the most common invasive type (other names: NST/NOS).

  • Lobular carcinoma has a very variable clinical evolution, from indolent to aggressive: 10-15% of cases.

    • frequently expresses loss of E-cadherin;

    • frequently bilateral cancer;

    • it has a particular mode of tissue invasion, called “the Indian filling”, being difficult to diagnose using mammography or palpation.

  • Papillary, mucinous, tubular, cribriform carcinoma (luminal types): favorable prognosis (80% survival at 10 years).

  • Micropapillary carcinoma: frequently lymphatic and vascular invasion, frequently systemic recurrence.

  • Lobular pleiomorphic carcinoma (luminal type): poor prognosis.

  • Carcinoma: cystic adenoid, medullary, low-grade squa­mous, secretory (triple negative type) – excellent prog­nosis.

  • Inflammatory carcinoma: 1% of cancers, very ag­gres­sive, being associated with local skin erythema that can mimic mastitis and “orange peel” skin edema.

  • Paget’s disease of the breast is often associated with a DCIS.

  • Phyllodes tumor: 90% are benign, 10% are malignant

    • it does not metastasize at a distance (or pulmonary, sarcomatoid pattern);

    • local recurrences frequently occur.

  • Squamous cell carcinoma, lymphoma or angiosarcoma(4).

3. Molecular classification (subtypes)

  • Luminal A: estrogen receptors (ER) positive; pro­ges­te­rone receptors (PGR) positive; Ki67 score low; HER2 gene expression negative.

  • Luminal B: ER positive, PGR negative/positive, high Ki67 score, HER2 gene expression positive or negative.

  • Overexpressed HER2: 20% of breast cancers

    • low expression of ER and PGR (<10%), or negative;

    • high Ki67 score.

  • Basaloid type – triple-negative cancers: negative ER and PGR, negative HER2 gene expression(5).

4. Screening

  • For the age of 50-70 years old, in women without risk factors present, a mammogram will be performed once every two years.

  • The benefit brought is represented by the decrease of mortality, as follows: between 50-59 years old – by 14%; between 60-69 years old – with 33%.

  • It decreases the incidence of lymph node invasion and advanced local cancer.

  • Between 1-7% of mammograms are false positive.

  • Breast MRI is recommended for the population with risk factors: BRCA1/2 mutation.

  • First-degree relatives with BRCA1/2 mutation.

  • 20-25% lifetime risk, calculated by tools: Tyrer-Cuzick, Gail or Claus model.

  • Chest radiotherapy due to other cancers.

  • Genetic syndromes: Li-Fraumeni, Cowden, or their diagnosis in one of the first-degree relatives.

  • Recommendation for performing MRI: annual and biannual mammography 10 years earlier than the age of diagnosis of cancer in a first-degree relative.

  • MRI recommendation for certain situations:

    • lobular carcinoma in situ; ductal carcinoma in situ;

    • atypical lobular/ductal hyperplasia;

    • very dense or uneven breasts (seen on mammography or breast ultrasound)(6).

5. Diagnosis

  • Clinically possible:

    • paving table – solitary, unilateral, solid, hard, irregular, painless, woody consent;

    • skin and nipple retraction;

    • changes in breast size, uneven;

    • nipple discharge;

    • inflammatory carcinoma – erythema/edema of the skin with or without the appearance of orange peel (at least 1/3 of the breast, or the whole breast);

    • high tumor mass usually present in the breast;

    • Paget disease – around the nipple, which appears ulcerated;

    • in 90% of cases it is a carcinoma in situ;

    • less than 5% of breast cancer cases are Paget’s disease.

  • Initial assessment:

    • family history and pathological issues;

    • menopausal status;

    • blood tests – hemogram and biochemistry (do­sage of tumor markers is not recommended); if un­jus­ti­fied cytopenia occurs, spinal cord aspiration is recommended;

    • evaluation of cardiac function (if treatment with anthracyclines or anti-HER2 antibodies is planned);

    • for tumor evaluation – palpation physical exa­mi­na­tion, mammography, breast ultrasound, breast MRI;

    • for the evaluation of metastatic disease, if the patient is in an intermediate or high-risk group, then we should perform CT scan of chest, abdomen and pelvis or MRI of abdomen and pelvis and CT chest or bone scintigraphy for: invaded ganglia, tumor >5 cm, signs and symptoms for the presence of metastases, aggressive histology.

PET-CT is not recommended in stages cI, cII, ope­ra­ble IIIA, but it is useful in discovering unidentified me­tastases on CT or MRI.

  • Biopsy

Confirmation of malignancy must precede any therapeutic act:
  • with thick needle or vacuum-assisted biopsy, guided by ultrasound or MRI;

  • it is recommended to place a “marker” instead of the biopsy;

  • if at biopsy the result obtained by im­mu­no­his­to­chemistry techniques is of triple-negative carcinoma, the IHC analysis will be repeated from the specimen obtained at the operation;

  • excisional biopsy.

  • Armpit

    • axillary ultrasound will be performed before any kind of treatment;

    • if suspicious lymph nodes are found, fine needle aspiration or thick needle biopsy is recommended for confirmation;

    • if no suspicious lymph nodes are found, the sentinel node technique will be performed (gold standard for patients with negative axillary ultrasound);

    • contraindication for the sentinel node – locally advanced disease or inflammatory carcinoma;

  • The histopathological examination must specify:

    • the histopathological type;

    • the level of invasion (invasive or in situ);

    • degree of differentiation (G1 – well differentiated; G2 – moderately differentiated; G3 – poorly dif­fe­ren­tiated);

    • hormone receptor status (by immunohistochemistry techniques);

    • HER2 mutation status (by immunohistochemistry techniques and confirmation by FISH/CISH)

    • resection margins infiltrated or not;

    • tumor dimension;

    • lymph node status, report on the number of in­vaded lymph nodes/number of examined lymph nodes;

    • TNM pathologic stadialization(7).

6. TNM system for breast cancer

Tumor (T)

Using the TNM system, the “T” plus a letter or number (0 to 4) is used to describe the size and location of the tumor. Tumor size is measured in centimeters (cm). A centimeter is roughly equal to the width of a standard pen or pencil.

Stage may also be divided into smaller groups that help describe the tumor in even more detail. Specific tumor stage information in listed below.

TX: The primary tumor cannot be evaluated.

T0 (T plus zero): There is no evidence of cancer in the breast.

Tis: It refers to carcinoma in situ. The cancer is confined within the ducts of the breast tissue and has not spread into the surrounding tissue of the breast. There are two types of breast carcinoma in situ:

  • Tis (DCIS) – DCIS is a noninvasive cancer, but if not removed, it may develop into an invasive breast cancer later. DCIS means that cancer cells have been found in breast ducts and have not spread past the layer of tissue where they began.

  • Tis (Paget’s) – Paget disease of the nipple is a rare form of early, noninvasive cancer that is only in the skin cells of the nipple. Sometimes, Paget disease is associated with an invasive breast cancer. If there is an invasive breast cancer, it is classified according to the stage of the invasive tumor.

T1: The tumor in the breast is 20 millimeters (mm) or smaller in size at its widest area. This is a little less than an inch. This stage is then divided into four substages depending on the size of the tumor:

  • T1mi is a tumor that is 1 mm or smaller.

  • T1a is a tumor that is larger than 1 mm but 5 mm or smaller.

  • T1b is a tumor that is larger than 5 mm but 10 mm or smaller.

  • T1c is a tumor that is larger than 10 mm but 20 mm or smaller.

T2: The tumor is larger than 20 mm but not larger than 50 mm.

T3: The tumor is larger than 50 mm.

T4: The tumor falls into one of the following groups:

  • T4a means the tumor has grown into the chest wall.

  • T4b is when the tumor has grown into the skin.

  • T4c is cancer that has grown into the chest wall and the skin.

  • T4d is inflammatory breast cancer.

Node (N)

The “N” in the TNM staging system stands for lymph nodes. These small, bean-shaped organs help fight infection. Lymph nodes near where the cancer started are called regional lymph nodes. Regional lymph nodes include:

  • Lymph nodes located under the arm, called the axillary lymph nodes.

  • Lymph nodes located above and below the collarbone.

  • Lymph nodes located under the breastbone, called the internal mammary lymph nodes.

Lymph nodes in other parts of the body are called distant lymph nodes. The information below describes the staging.

NX: The lymph nodes were not evaluated.

N0: Either of the following:

  • No cancer was found in the lymph nodes.

  • Only areas of cancer smaller than 0.2 mm are in the lymph nodes.

N1: The cancer has spread to one to three axillary lymph nodes and/or the internal mammary lymph nodes. If the cancer in the lymph node is larger than 0.2 mm but 2 mm or smaller, it is called “micrometastatic” (N1mi).

N2: The cancer has spread to 4 to 9 axillary lymph nodes. Or, it has spread to the internal mammary lymph nodes, but not the axillary lymph nodes.

N3: The cancer has spread to 10 or more axillary lymph nodes, or it has spread to the lymph nodes located under the clavicle, or collarbone. It may have also spread to the internal mammary lymph nodes. Cancer that has spread to the lymph nodes above the clavicle, called the supraclavicular lymph nodes, is also described as N3.

If there is cancer in the lymph nodes, knowing how many lymph nodes are involved and where they are helps doctors to plan treatment. The pathologist can find out the number of axillary lymph nodes that contain cancer after they are removed during surgery. It is not common to remove the supraclavicular or internal mammary lymph nodes during surgery. If there is cancer in these lymph nodes, treatment other than surgery, such as radiation therapy, chemotherapy and hormonal therapy, are generally used.

Metastasis (M)

The “M” in the TNM system describes whether the cancer has spread to other parts of the body, called distant metastasis. This is no longer considered early-stage or locally advanced cancer.

MX: Distant spread cannot be evaluated.

M0: There is no evidence of distant metastases.

M0 (i+): There is no clinical or radiographic evidence of distant metastases. However, there is microscopic evidence of tumor cells in the blood, bone marrow, or other lymph nodes that are no larger than 0.2 mm.

M1: There is evidence of metastasis to another part of the body, meaning there are breast cancer cells growing in other organs.

Stages

Stage 0: Stage zero (0) describes the disease that is only in the ducts of the breast tissue and has not spread to the surrounding tissue of the breast. It is also called noninvasive or in situ cancer (Tis, N0, M0).

Stage IA: The tumor is small, invasive, and has not spread to the lymph nodes (T1, N0, M0).

Stage IB: Cancer has spread to the lymph nodes and the cancer in the lymph node is larger than 0.2 mm, but less than 2 mm in size. There is either no evidence of a tumor in the breast, or the tumor in the breast is 20 mm or smaller (T0 or T1, N1mi, M0).

Stage IIA – any one of these conditions:

  • There is no evidence of a tumor in the breast, but the cancer has spread to one to three axillary lymph nodes. It has not spread to distant parts of the body (T0, N1, M0).

  • The tumor is 20 mm or smaller and has spread to one to three axillary lymph nodes (T1, N1, M0).

  • The tumor is larger than 20 mm but not larger than 50 mm and has not spread to the axillary lymph nodes (T2, N0, M0).

Stage IIB – either of these conditions:

  • The tumor is larger than 20 mm but not larger than 50 mm and has spread to one to three axillary lymph nodes (T2, N1, M0).

  • The tumor is larger than 50 mm but has not spread to the axillary lymph nodes (T3, N0, M0).

Stage IIIA: The cancer of any size has spread to 4 to 9 axillary lymph nodes or to internal mammary lymph nodes. It has not spread to other parts of the body (T0, T1, T2, or T3; N2; M0). Stage IIIA may also be a tumor larger than 50 mm that has spread to one to three axillary lymph nodes (T3, N1, M0).

Stage IIIB: The tumor has spread to the chest wall or caused swelling or ulceration of the breast, or it is diagnosed as inflammatory breast cancer. It may or may not have spread to up to 9 axillary or internal mammary lymph nodes. It has not spread to other parts of the body (T4; N0, N1, or N2; M0).

Stage IIIC: A tumor of any size that has spread to 10 or more axillary lymph nodes, the internal mammary lymph nodes, and/or the lymph nodes under the collarbone. It has not spread to other parts of the body (any T, N3, M0).

Stage IV (metastatic): The tumor can have any size and has spread to other organs, such as the bones, lungs, brain, liver, distant lymph nodes, or chest wall (any T, any N, M1). Metastatic cancer found when the cancer is first diagnosed occurs about 6% of the time. This may be called de novo metastatic breast cancer. Most commonly, metastatic breast cancer is found after a previous diagnosis of early breast cancer(8).

7. Breast cancer treatment

a) DCIS (ductal in situ carcinoma); noninvasive lesion (which did not extend beyond the basement membrane) but malignant.

  • one-third of the cases recur at 10-15 years if the lesion is only excised; the recurrence comes in the form of invasive carcinoma in 50% of cases;

  • local treatment: mastectomy or tumorectomy with free edges without axial lymph node dissection;

  • if the disease is multicenter, a simple total mastectomy is recommended;

  • radiotherapy (RT) is recommended after tumorectomy with 50 Gy DT;

  • a negative edge is considered >1 cm in all directions;

  • radiotherapy can be excluded if the edges are free and the tumor is a low-grade one;

  • the excision of the sentinel nodule is recommended in case of papular tumor mass with biopsy and diagnosis of DCIS, multiple areas of diffuse pluricentric calcifications, large and diffuse tumors;

  • systemic treatment: tamoxifen 10 mg x 2/day for 5 years;

  • the benefit is 6% absolute risk reduction in the ipsi­la­te­ral breast and 5% risk reduction in the contralateral one;

  • for postmenopausal patients, AI (anastrozole, letrozole) is a possible TAM substitute (according to NSABP study B-35).

b) LCIS – non-malignant lesion but which increases the risk of invasive cancer:

  • it is muticentric and 30% are bilateral cases;

  • for this reason, the conservative treatment is not recommended, but unilateral or bilateral mastectomy with immediate reconstruction or observation by annual mammography;

  • chemoprevention can be done with tamoxifen/raloxifene.

8. Treatment of operable breast cancer

  • This category includes stages I, II and some tumors in stage IIIA, where surgery is considered optimal as the first stage of treatment.

  • The general assessment and the evaluation of the tumor are made according to the principles mentioned at point 5.

a) Surgery

  • conservative treatment (BCT) + radiotherapy has a recurrence rate of 14%, according to EORTC 10801 study, at 20 years;

  • contraindications: thoracic radiotherapy history that cumulated with the dose for breast radiotherapy would exceed 70 Gy DT;

  • radiotherapy to be administered during pregnancy;

  • multifocal, multicenter cancer;

  • diffuse malignant microcalcifications on mam­mo­graphy;

  • preexisting connective tissue disease (scleroderma or lupus);

  • tumors >5 cm or tumor/breast size ratio (e.g., small breast and large tumor) – relative contraindication;

  • BRCA1/2 positive (it requires bilateral mastectomy);

  • central quadrant tumor (relative contraindication);

  • example: B-plasty; Donut mastopexy; Snowman technique;

  • radical mastectomy: recurrence at 20 years of 5% according to NSABP B-06;

  • for those who do not want to perform radiotherapy or there are contraindications for BCT/RT;

  • it involves breast removal ± axillary lymphadenectomy (modified mastectomy);

  • sentinel node (SLN): it represents the first node in which the lymphatic drainage goes directly from the primary tumor;

  • gold standard for cN0;

  • the colloid is injected with technetium or blue dye which is captured by the ganglion;

  • if it is positive, only the nodes of stations I and II are excised;

  • contraindication: local advanced breast cancer (T3, T4) or inflammatory;

  • multicentric tumors;

  • palpable or invaded axillary lymph nodes proven by biopsy;

  • ALDN: axillary lymphadenectomy;

  • it is done in addition to >3 positive SLNB ganglia or in cN1 + patients;

  • breast reconstruction: immediate or delayed;

  • with silicone implants or saline solution, or autolo­gous;

  • contraindications: metastatic disease, fibrosis after RT breast, inflammatory breast cancer.

b) Post-BCT radiotherapy

It reduces the risk of local recurrence by 70% at 5 years:

  • conventional – 45-50 Gy (1.8-2 Gy/fraction) DT for a period of 5 weeks;

  • hypofractionated – 42.5 Gy DT in three weeks, indications – age >50 years old;

  • tumors <5 cm, pN0;

  • no need for neo-/adjuvant chemotherapy ad­mi­nis­tration;

  • boost applies to young patients <40 years old; 10-16 Gy DT, 2 Gy/fr at high risk of local recurrence;

  • axillary irradiation after SLN or ALDN after BCT: not necessary in pN0.

c) Post-mastectomy radiotherapy

  • recommended for the prevention of local recurrences in the order of occurrence: I) chest wall; II) supraclavicular/infraclavicular; III) axillary;

  • recommended for:

    • pT3pN1 or stage III;

    • more than 4 nodes invaded;

    • positive margins;

    • broken lymph node capsule.

  • in the situation of the presence of 1-3 invaded nodes, axillary radiotherapy (RT) is recommended (in addition to thoracic RT) for the cases: poorly differentiated G3, age <35 years old, less than 10 examined nodes, extracapsular extension present;

  • in case of a complete pathological response (pCR) after neoadjuvant chemotherapy, it is recommended to perform RT for: cT3/4, cN+; or other high risk factors (young age, aggressive histology at biopsy, G3);

  • in case of the need to administer the adjuvant treatment with chemotherapy, RT will be performed in addition after its completion; I confirm the aforementioned criteria or interspersed if there is the presence of numerous risk factors;

  • irradiation to the chest wall is recommended with DT 40 Gy during 4 weeks;

  • irradiation of regional ganglia and armpit is done with DT 50 Gy, in fractions of 1.8-2Gy/fr.

d) Adjuvant/neoadjuvant treatment

Several principles have been established, depending on the subtype of breast cancer, as follows:

Luminal A – hormone therapy (exception: multiple lymph nodes invaded, T3/T4 – chemotherapy will be added).

Luminal B – chemotherapy + hormone therapy.

Luminal B + HER2 – chemotherapy + anti-HER2 therapy + hormone therapy.

Overexpressed HER2 – chemotherapy + anti-HER2 therapy.

Triple negative – chemotherapy.

The adjuvant treatment is preferably started 3-6 weeks after surgery.

All A/B luminal cancers must receive hormone the­rapy.

All HER2-positive cancers must receive anti-HER treatment.

In the case of ER-positive, HER2-negative cancers, the need for chemotherapy can be evaluated by molecular tests, such as OncotypeDX, MammaPrint, and Prosigma, which estimate the risk of recurrence, testing performed on tissue.

Chemotherapy

It is associated with a decrease in the annual risk of relapse and death.

DD (dose-dense) administration has increased the time to recurrence and the overall survival of the an­thra­cycline and taxane regimen, along with gra­nu­lo­cyte growth factor, and is recommended for cases with in­ter­mediate and high risk.

For the preservation of fertility, ovarian suppression agents can be associated, such as LHRH analogues (goserelin).

Example:

  • FAC/CAF (fluorouracil/doxorubicin/cyclo­phos­pha­mide).

  • FEC/CEF (fluorouracil/epirubicin/cyclophosphamide).

  • CMF (cyclophosphamide/methotrexate/fluorouracil).

  • AC followed by docetaxel at 3 weeks.

  • Other chemotherapy regimens:

  • AC followed by paclitaxel at 3 weeks.

  • EC (epirubicin/cyclophosphamide).

  • FEC followed by T (fluorouracil/epirubicin/cyclophosphamide followed by docetaxel).

  • Dose-dense AC (doxorubicin/cyclophosphamide) followed by paclitaxel at 2 weeks.

  • AC (doxorubicin/cyclophosphamide) followed by weekly paclitaxel.

  • CT (docetaxel/cyclophosphamide).

  • AC (doxorubicin/cyclophosphamide).

Hormonotherapy:

  • all luminal subtypes must be treated with endocrine therapy, in case of use of chemotherapy, immediately after its completion;

  • the use of tamoxifen (TAM) or aromatase inhibitors (AI) is not recommended in parallel with chemotherapy;

  • there are differences between pre- and postmenopausal patients;

  • menopause involves bilateral ovorectomy or age over 60 years old and more than 12 months of amenorrhea;

  • in patients younger than 60 years old, estradiol and FSH levels should be checked (including if the patient has amenorrhea secondary to chemotherapy) to determine the patient’s status;

  • for premenopausal women, the standard is the use of tamoxifen 20 mg/day ± ovarian suppression (drug or surgical) in patients with intermediate or high risk; the optimal duration of ovarian suppression is not known;

  • tamoxifen can be used for a period of 5 years, or extended up to 10 years (benefit on overall survival);

  • for premenopausal patients with a high risk of recurrence, the combination exemestan 25 mg/day + effective ovarian suppression can be used;

  • for postmenopausal women, non-steroidal aromatase inhibitors (letrozole 2.5 mg/day or anastrozole 1 mg/day) or steroids (exemestane 25 mg/day) are of choice for a period of 5 years;

  • tamoxifen can also be used after menopause, becoming a “switch” after 2-3 years with an aromatase inhibitor;

  • exceeding 5 years with aromatase inhibitors is not the standard, because it brings minimal survival benefits;

  • the evaluation by bone densitometry is recommended in patients treated with AI and additional Ca and vitamin D, and in those on tamoxifen, with the evaluation of the risk of thromboembolic events and endometrial hyperplasia (with low risk of transformation into endometrial cancer);

  • in patients with low circulating estrogen levels, caused by ovarian suppression or hormone therapy, the administration of zoledronic acid prolongs the sur­vival and the time to recurrence.

Anti-HER2 therapy:

  • one year of trastuzumab is the standard for tumors >1 cm, associated with chemotherapy, and then maintenance with trastuzumab;

  • for tumors >0.5 cm, trastuzumab brings benefits, associating only with taxanes;

  • trastuzumab should not be combined with an­thra­cyclines due to cardiac toxicity, but may be used con­co­mitantly with taxanes;

  • before initiating therapy, it is recommended to perform a cardiological consultation, then once every three months while the patient receives treatment;

  • trastuzumab may be associated with adjuvant radiotherapy;

  • double blockade with trastuzumab and pertuzumab is recommended for patients with high-risk factors (invaded lymph nodes, no hormone receptors, locally advanced); this combination did not increase the risk of cardiac events;

  • trastuzumab and pertuzumab can be used con­co­mi­tantly with taxane-based or sequential chemotherapy;

  • chemotherapy regimens are presented above; anthracycline therapy is recommended in patients with risk factors (if there are contraindications it is replaced with a platinum salt carboplatin in combination with a taxane);

  • in case of residual disease after neoadjuvant anti-HER2 therapy, it can be continued with T-DM1* up to one year of treatment;

  • extended therapy with neratinib*, for another one year in adjuvant, brought benefits especially in the category of patients with positive hormone receptors, with adequate control of diarrhea.

Doses: trastuzumab 8 mg/kg – loading dose, then 6 mg/kg every 3 weeks or 4 mg/kg every 2 weeks;
pertuzumab 840 mg – loading dose, then 420 mg every 3 weeks.

T-DM1: 3.6 mg/kg at 3 weeks.

Neratinib: 120 mg/day in week 1, 160 mg/day in week 2, and 240 mg/day in weeks 3-52 + loperamide.

* In Romania, at present, T-DM1 and neratinib are not reimbursed(9) for the treatment of inoperable/advanced breast cancer locally.

  • there are included patients in stages IIIA (except for T3N1M0), IIIB and IIIC, which require neoadjuvant treatment to be converted to operability or to perform conservative therapy (sector + RT);

  • the treatment regimens are the same as those used in adjuvant in combination with trastuzumab or double-blocker anti-HER2 (for HER2-positive disease) with continuation of anti-HER2 agents for up to one year or replacement with T-DM1 in case of residual disease in patients in whom no double-blockade was performed in the neoadjuvant;

  • it is recommended to administer all the doses plan­ned before the operation, without being divided peri­operatively;

  • the addition of platinum salt in triple negative disease has brought benefits regarding full response rates;

  • platinum salt can also be recommended for patients with BRCA1/2 mutations;

  • if a complete pathological response is not obtained after neoadjuvant administration of anthracycline-taxane, in triple negative disease, oral capecitabine is recommended for six adjuvant cycles;

  • in patients with lobular histology, luminal A, post­me­no­pausal, it is possible to opt for neoadjuvant treat­ment with aromatase inhibitor for 4-8 months.

9. Monitoring

  • in the first 3 years, the evaluation of the patients is done every 3-6 months, and after 3 years, at 6-12 months;

  • monitoring consists of anamnesis, clinical examination and usual biological tests;

  • mammographic evaluation is done at 1-2 years, the first mammography being indicated 6-12 months after the end of radiotherapy or chemotherapy;

  • the routine use of tumor markers and imaging evaluations (X-ray, CT, MRI, bone scintigram) is not recommended in patients without suspicion of relapse;

  • for patients undergoing TAM treatment, an annual gynecological examination is recommended.

10. Treatment of relapsed/metastatic disease

Principles:

  • repeat the biopsy to confirm the origin of the metastasis;

  • repetition of all metastasis biomarkers – ER, PgR, HER2, PIK3CA etc.;

  • all patients should be referred for clinical trials;

  • MSI can be tested and recommended in some patients especially for the use of immunotherapy – it is not routine;

  • all positive ER, PgR patients should receive hormone therapy ± chemotherapy (in case of visceral crisis) and HER2 negative: CDK4/6 inhibitors (as appropriate) + hormone therapy;

  • for premenopausal patients with positive ER, ovo­rec­tomy or ovarian suppression therapy is recommended;

  • for HER2-positive patients, anti-HER2 treatment + chemotherapy/hormone therapy is administered;

  • for patients with triple negative disease, sequential chemotherapy will be administered, instead of combinations of cytostatics because they had the same overall survival;

  • BRCA 1/2 mutation test;

  • for M1OSS (bone metastases), bisphosphonates or denosumab will be administered;

  • the goal is to increase the quality of life and prolong survival.

a) Endocrine therapy: 

  • the selection of the treatment will be based on the adjuvant therapy used and the time elapsed from its completion to progression and menopausal status;

  • hormone therapy is of choice for patients who are not in a visceral crisis or with life-threatening symptoms (e.g., dyspnea that does not respond to thoracentesis);

  • in premenopause, historically, tamoxifen monotherapy can be used;

  • obligatory suppression of ovarian function (SFO) (with LHRH [leuprolide] agonists/GNRH analogues [goserelin] or ovarectomy) – estradiol, LH and FSH will be dosed for verification;

  • the addition of CDK 4/6 inhibitors has prolonged survival and is the standard in the treatment of hormone receptor cancer**;

Variants: TAM + OFS or AI + palbociclib/ribociclib/abemaciclib + OFS in line I.

Faslodex + palbiciclib/ribociclib/abemaciclib + OFS in line II.

In postmenopause: AI + palbociclib/ribociclib/abemaciclib in line I.

Faslodex + palbociclib/ribociclib/abemaciclib in line II.

Abemaciclib 200 mg p.o. x 2/day – monotherapy for patients treated with endocrine therapy or chemotherapy.

Dosage:

  • Palbociclib CDK 4/6 inhibitor, 125 mg/21 days + AI/fulvestrant.

  • Ribociclib CDK 4/6 inhibitor, 600 mg/21 days + AI/fulvestrant.

  • Abemaciclib CDK 4/6 inhibitor, with higher specificity for CDK4 inhibition.

§ 150 mg BID + fulvestrant.

§ 200 mg BID monotherapy.

§ 150 mg BID + AI.

** In Romania, at present, the drugs reimbursed in the first line are palbociclib and ribociclib, and in the second line – palbociclib.

For patients with PIK3CA mutation and exposed to an AI, the combination of alpelisib*** (300 mg/day) + Faslodex® 500 mg/4 weeks can be used.

In subsequent lines, everolimus*** (mTOR inhibitor) 10 mg/day + exemestane 25 mg/day can be used.
***In Romania, at present, none of the therapies is reimbursed in the treatment of metastatic breast cancer.
Other variants taking into account that have been used previously:

  • Faslodex® 500 mg/4 weeks (in line II).

  • Faslodex® + AI in line I.

  • Megestrol acetate 40 mg/day

  • Low estrogen doses.

b) Chemotherapy:

  • no survival benefit has been demonstrated for the combination of two substances versus their sequencing in monotherapy (unless a quick response is desired);

  • it is recommended in positive ER/PGR disease in patients with visceral crisis or after using all varieties of endocrine treatment (endocrine resistance);

  • the first line is associated with a longer response period than the following lines;

  • the response to the first line of chemotherapy is a surrogate prognostic factor for the time to progression and the overall survival;

  • the choice of first-line agents depends on the treatment performed in the adjuvant, from the elapsed time to progression/recurrence, patient preference, and associated comorbidities.

  • if the elapsed time from the end of the adjuvant to the recurrence is >18-24 months, it can be recharged with the same substances; if the elapsed time is <1 year, it is preferable to change the regime;

  • eribulin, a non-taxane inhibitor of microtubules, has shown survival benefit after using more than two lines of treatment;

  • Nab-paclitaxel, taxol with albumin-dependent na­no­par­ticles, does not contain solvent and reduces ana­phy­lac­tic reactions, and does not require steroid premedication (dose: 260 mg/m2 every 3 weeks);

  • Ixabepilone, a non-taxane microtubule stabilizer, is used when taxane resistance occurs, approved in combination with capecitabine or monotherapy in patients refractory to anthracyclines, taxanes or capecitabine.

  • anti-angiogenic therapy with bevacizumab, in combination with paclitaxel, prolonged the time to progression, but not the survival.

  • Preferred monotherapy regimens:

  • anthracyclines (doxorubicin, epirubicin, liposomal doxorubicin) – taxanes (paclitaxel, docetaxel);

  • antimetabolites (capecitabine, gemcitabine);

  • other microtubule inhibitors (vinorelbine).

  • Other monotherapy regimens:

  • cyclophosphamide – mitoxantron

  • cisplatin/carboplatin

  • etoposide

  • vinblastine

  • fluorouracil

  • ixabepilone.

  • Preferred polychemotherapy regimens:

  • CAF/FAC (cyclophosphamide/doxorubicin/fluo­ro­uracil) – FEC (cyclophosphamide/epirubicin/fluoro­uracil)

  • AC (doxorubicin/cyclophosphamide)

  • EC (epirubicin/cyclophosphamide)

  • AT (doxorubicin/docetaxel or paclitaxel)

  • CMF (cyclophosphamide/methotrexate/fluorouracil)

  • docetaxel/capecitabine

  • GT (gemcitabine/paclitaxel)

  • etoposide + cisplatin.

  • Other combinations:

  • ixabepilone + capecitabine.

c) Immunotherapy:

  • atezolizumab**** 840 mg in combination with nab-paclitaxel 100 mg/m2 for patients with triple-negative disease, locally advanced inoperable or metastatic, with PD-L1 expression >1%.

  • sacituzumab govitecan**** 10 mg/kg day 1 and day 8 (combination of irinotecan with anti-antigen 2 antibody on the surface of trophoblastic cells) for triple negative patients, after more than two lines of treatment.

d) Anti-HER2 therapy:

  • trastuzumab + pertuzumab + taxane is the first-line stan­dard for previously untreated patients with anti-HER2 or who have progressed after adjuvant therapy for more than 12 months after termination; the therapy is continued until disease progression or unacceptable toxicity; the combination can also be used with an AI for patients with positive hormone receptors;

  • T-DM1 (ado-trastuzumab emtamsine) 3.6 mg/kg/3 weeks is approved in line II, after progression to trastuzumab;

  • trastuzumab deruxtecan**** 5.4 mg/kg in anti-HER2 multilayer patients, with a median duration of response of 14.8 months;

  • lapatinib (tyrosin kinase inhibitor) 1250 mg/day + capecitabine 1000 mg/m2 BID/day/14 days for patients previously treated with anthracycline, taxanes and trastuzumab;

  • tucatinib**** 300 mg BID + trastuzumab + capecitabine for previously treated patients with double blockade of anti-HER2 and T-DM1, with survival benefit inclusive in the subgroup of patients with brain metastases.

e) PARP inhibitors:

  • for patients with BRCA 1/2 mutations, excluding those with HER2 overexpression;

  • Examples:

  • olaparib**** 300 mg BID, until disease progression or unacceptable toxicity;

  • talazoparib**** 1 mg/day, until disease progression or unacceptable toxicity.

Both have improved time to disease progression; the survival data are not yet mature.

**** In Romania, at present, these therapies are not reimbursed or approved (except for olaparib).

f) Bone-modifying agents:

  • denosumab and zoledronic acid increase the time to fracture in patients with bone metastases and are recommended to be administered monthly and, after one year, at every 3 months, with the same benefit but with a lower risk of mandibular osteonecrosis.

g) Surgery:

  • primary tumor surgery in the metastatic stage has been shown to reduce survival;

  • the patients with a single or few brain metastases should be referred to surgery (preferably stereotactic) and then radiation therapy; in HER2-positive patients with only cerebral progression and stable extracranial disease, no change in treatment regimen is recommended;

  • the surgical treatment of liver metastases should be performed in patients without extrahepatic disease, in which the disease is proven to be controlled and the metastases are limited in number and size;

  • for patients with pleural metastases, for the control of talc symptoms;

  • it is recommended for palliative purposes in any situation in which surgery could increase the quality of life of the patients.

h) Radiotherapy:

  • it is recommended for palliative purposes for the control of the symptoms of brain metastases, in the control of bone metastasis pain, for the prevention or treatment of spinal cord compression, and for bleeding of skin metastases.

i) Monitoring:

  • treatment monitoring is done once every 2-4 months from the initiation of a new therapeutic regimen using the techniques initially used for imaging (CT, MRI) or PET-CT;

  • monitoring the adverse effects of the treatment and managing according to the supportive treatment guidelines.

11. Special situations

a) Breast cancer in pregnancy:

  • breast biopsy in pregnancy is safe and should be performed whenever there is a suspicion;

  • radical mastectomy is used in the first and second trimesters;

  • tumorectomy + ALND + RT can be performed in the third trimester, with RT performed after birth;

  • chemotherapy is administered in the second and third trimesters;

  • there is no risk-free regime in pregnancy;

  • paclitaxel is teratogenic and should NOT be used during pregnancy;

  • the four-cycle AC regimen was used safely, once every 3 weeks in neoadjuvant/adjuvant in trimester II/III;

  • avoid thrombocytopenia and neutropenia near birth;

  • granulocyte growth factors can be used in case of need, but there is no sustained evidence about them;

  • anti-HER2 agents such as trastuzumab have been shown to cause oligohydraminoosis and fetal renal failure and should NOT be used during pregnancy;

  • tamoxifen is teratogenic and should not be used during pregnancy.

b) Breast cancer in men:

  • risk factors – BRCA 1/2, Klinefelter syndrome, history of chest wall irradiation;

  • mastectomy is often used because the breast is small and a sector would not be indicated;

  • the same chemotherapy and hormone therapy guidelines are used as for women;

  • tamoxifen is of choice, 20 mg x 2/day.

  • if an AI is needed, an orchiectomy or LHRH agonist is associated.

c) Phyllodes:

  • local treatment consists of excision with wide edges (>1 cm), without axillary lymphadenectomy;

  • total mastectomy is indicated in cases where ap­pro­priate free margins cannot be obtained;

  • postoperative radiotherapy on the breast or chest wall is controversial;

  • chemotherapy and hormone therapy do not have benefits;

  • in case of metastases (usually lung), a treatment si­milar to that of soft tissue sarcomas is recommended.

d) Paget’s disease:

  • Paget’s disease ± DCIS has indication for mastectomy ± axillary lymphadenectomy or excision of the mammary tumor formation and of the nipple-areolar complex (CMA), followed by RT in the whole breast and optionally the additional dose on the tumor bed;

  • invasive breast carcinoma and Paget’s disease are indicated for mastectomy + axillary lymphadenectomy or excision of the mammary tumor formation and CMA + axillary lymphadenectomy + breast RT ± additional dose on the tumor bed;

  • postoperatively, adjuvant treatment is performed according to the tumor staging;

  • in cases without invasive carcinoma or associated DCIS, tamoxifen is recommended to reduce the risk of invasive cancer(9).

Bibliografie

  1.  Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, et al. Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019; 30(8):1194–220.

  2.  https://www.breastcancer.org/risk/factors/genetics

  3.  Sun YS, Zhao Z, Yang ZN, Xu F, Lu HJ, Zhu ZY, Shi W, Jiang J, Yao YPP, Zhu HP. Risk Factors and Preventions of Breast Cancer. Int J Biol Sci. 2017; 13(11): 1387–1397. doi: 10.7150/ijbs.21635

  4. Oluogun WA, Adedokun KA, Oyenike MA, Adeyeba OA. Histological classification, grading, staging, and prognostic indexing of female breast cancer in an African population: A 10-year retrospective study. Int J Health Sci (Qassim). 2019 Jul-Aug; 13(4): 3–9.

  5. Al-Thoubaity FK. Molecular classification of breast cancer: A retrospective cohort study. Ann Med Surg (Lond). 2020 Jan; 49: 44–48. 

  6. https://www.cancer.gov/types/breast/patient/breast-screening-pdq 

  7. https://www.cancer.gov/types/breast/hp/breast-treatment-pdq#_6_toc 

  8. https://www.cancerresearchuk.org/about-cancer/breast-cancer/stages-types-grades/tnm-staging

  9. https://www.cancer.gov/types/breast/hp/breast-treatment-pdq 

  10. Cardoso F, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rubio IT, Zackrisson S, Senkus E. Early Breast Cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2019; 30: 1194-1220. 

  11. Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, André F, Harbeck N, Aguilar Lopez B, Barrios CH, Bergh J, Biganzoli L, Boers-Doets CB, Cardoso MJ, Carey LA, Cortés J, Curigliano G, Diéras V, El Saghir NS, Eniu A, Fallowfield L, Francis PA, Gelmon K, Johnston SRD, Kaufman B, Koppikar S, Krop IE, Mayer M, Nakigudde G, Offersen BV, Ohno S, Pagani O, Paluch-Shimon S, Penault-Llorca F, Prat A, Rugo HS, Sledge GW, Spence D, Thomssen C, Vorobiof DA, Xu B, Norton L, Winer EP. 4th ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4). Ann Oncol. 2018; 29: 1634–1657.

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