6 BREAST CANCER

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BREAST CANCER
	· Epidemiology
· It is about 30% (or 1 in 3) of all new female cancers each year. The American Cancer Society's estimates for breast cancer in the United States for 2023 are: About 297,790 new cases of invasive breast cancer will be diagnosed in women. About 55,720 new cases of ductal carcinoma in situ (DCIS) will be diagnosed.
· Breast cancer is the second most common cancer among women in the United States (some kinds of skin cancer are the most common). Black women die from breast cancer at a higher rate than White women.
· lifetime risk is 1 in 8 for women who live to age 90 in the US
· + 95% are adenocarcinomas
· ER positive (HER2-negative; 50%-65% of cancers)
· HER2 positive (ER-positive or negative, 10%-20% of cancers)
· Triple negative (ER, PR and HER2 negative, 10%-20% of cancers)
	
RISK FACTORS
	· women
· in men only 1%
· aging
· + incidence after 30
· 75% of women with BC are over 50 years old
· previous exposure to ionizing radiation
· geographic factors
· + in the Americas and Europe
· - Asia and Africa
· 5x higher incidence and mortality rate in the US than in Japan
Diet, reproductive patterns and breastfeeding practices are believed to be involved. Accordingly, breast cancer rates seem to increase in regions of the world that are adopting Western habits.
· obesity and overweight
· because of exposure to estrogen produced by adipose tissue
· increases risk of ER+ tumors
· race and ethnicity
· + in European (+ RE+ incidence)
· Hispanic and African American
· develop aggressive tumors and at a younger age
· less than 150 minutes of moderate physical activity per week
· alcohol consumption
· factors related to reproductive life
· menarche before 12 years
· not have children
· first pregnancy after age 30
· menopause after age 55
Early age at menarche, nulliparity, lack of breastfeeding, and advanced age at first pregnancy are associated with increased risk, presumably because each of these factors increases the exposure of “at-risk” breast epithelial cells to estrogen stimulation.
· genetic mutations (tp53, BRCA1 AND BRCA2)
· family history
· + risk when 1st degree and at an early age
· BRCA1 and BRCA2 genetic alteration
	
PROTECTIVE FACTORS
	
1. Having children aged < 30 years
2. Breast-feeding
3. Physical activity
- 1 and 2 -> lower estrogen exposure and 3 -> still unknown protective mechanism
- Reduction in tumor incidence and recurrence (30 min/5xweek of moderate activity, after which there is no evidence of progressive increase in benefits)
	
INFLAMMATORY DISORDERS
	1. ACUTE MASTITISAlmost entirely, acute mastitis occurs in the first month of breastfeeding. Due to injuries such as mammary cracks, the breast is susceptible to bacterial infections (mainly by staphylococcus aureus). There is local erythema, pain, and often fever. If not treated, it can progress with abscesses, diffuse infection and even area of ​​necrosis. However, puerperal mastitis is easily treated with antibiotics and continued milk expression.
2. PERIDUCTAL MASTITISOr subareolar abscess, or squamous metaplasia of the milk ducts, or Zuska's disease. It affects women and men, notably smokers in 90% of cases. There is obstruction of the mammary duct by a keratin plug, and there may be accumulation of keratin in this duct and even secondary infection, which forms an abscess that tends to evolve into a fistula (generally at the top of the areola). During the acute condition, antibiotic therapy and drainage can be used, however, recurrence of the condition is common, and surgical removal of the duct and fistular tract is curative.
3. BREAST DUCTAL ECTASIAThis disorder presents with an ill-defined periareolar mass on palpation, often associated with thick, whitish papillary discharge. It is mainly found in multiparous women after the fifth decade of life, and mimics a carcinoma on mammography, due to its irregular appearance.
4. FAT NECROSISIt is usually a painless mass on palpation, which may show thickening or retraction of the skin. It has its largest audience in women who have already suffered breast trauma or previous surgeries.
5. LYMPHOCYTIC MASTOPATHYPapable hardened mass. They present atrophic collagen stroma, ducts and lobules. Clinically, it is of no importance other than to distinguish it from breast cancer. More common in women with type 1 diabetes and autoimmune thyroid disease.
6. GRANULOMATOUS MASTITISRare condition (less than 1%) of breast biopsies. They are caused by systemic granulomatous diseases, which rarely affect the breast. It can occur due to infection by mycobacteria or fungi, but also in a less prevalent way, in immunocompromised patients or users of breast piercings or prostheses. When limited to the lobes, it is uncommonly seen in women with parity.
	
BENIGN EPITHELIAL LESIONS
	
	
CLASSIFICATION
	❖95% adenocarcinomas❖Carcinoma in situ (neoplasm limited to the ducts and lobules by the basement membrane);❖Invasive (Penetrates from the membrane into the stroma, potentially infiltrates vessels, lymph nodes and distant sites).Breast carcinomas can be classified according to some parameters:
 
	
	HISTOLOGY
	CLINIC
	
CARCINOMA IN SITU (DCIS)
INTRADUCTAL
	· Histologically, subtypes: comedocarcinoma, solid, cribriform, papillary and micropapillary
	· Mammographic findings (calcifications); treatment with curative mastectomy in 95% of cases, which may be followed by irradiation.
	
LOBULAR CARCINOMA IN SITU (LCIS)
	· Cells devoid of E-cadine cell adhesion protein, almost always ER (estrogen receptor) positive.
	· Biopsy finding, bilateral in 20 to 40% of cases, more in young women; treatment of choice is prophylactic bilateral mastectomy, tamoxifen and clinical control
	
INVASIVE CARCINOMA, NO SPECIFIC TYPE (INT)
	· Hardened tumors, with an irregular border and a characteristic sound when cutting. Various histological features. With five gene expression patterns: luminal A, luminal B, normal-like, basal-like and HER2 positive.
	· 70 to 80% of carcinomas. Treatments depend on the TEN subtype and include hormonal treatments, chemotherapies, immunobiological agents.
	
INVASIVE LOBULAR CARCINOMA
	· Presence of non-cohesive infiltrative tumor cells, in single rows or sheets or clusters
	· It can be, like other breast cancers, well-differentiated, moderately-differentiated, and poorly-differentiated. The pattern of metastasis is different, it tends to occur in the peritoneum, meninges, gastrointestinal tract, uterus and ovaries.
	
CORDULAR CARCINOMA
	· It is usually soft on palpation, well circumscribed. It has a solid appearance, syncytium-like, large cells with a vesicular, pleomorphic nucleus and prominent nucleolus. All are little differentiated.
	· It can mimic a benign lesion, with very similar clinical and radiological characteristics. It usually has a better prognosis than NTE.
	
MUCINOUS CARCINOMA
	· Tumor soft or elastic, edges circumscribed, arranged in clusters and small islands within pools of mucin.
	· Present in elderly women, grows slowly, moderately differentiated and ER positive, better prognosis than NTE.
	
TUBULAR CARCINOMA
	· Exclusive to well-formed tubules. Myoepithelial layer absent. There is a cribriform pattern in some cases.
	· Most found in women in their late 40s, uncommon
	
INVASIVE PAPILLARY CARCINOMA
	· It can be micropapillary or papillary – the papillary ER being positive and the micropapillary being negative.
	· Rare. Favorable prognosis for the papillary and micropapillary leads to lymph node metastasis and poor prognosis.
	
METAPLASSIC CARCINOMA
	· Varied carcinomas, such as: squamous cell, with prominent spindle cell.
	· They are rare, less than 1%, they do not usually present lymph node metastases, but poor prognosis
	
PHYSIOPATHY
PATHOGENESIS EXPLANATION
	HEREDITARY BREAST CANCER
· Autosomal Dominant Trait
· The most important and most susceptible genes involved (BRCA1, BRCA2, TP53 and CHEK2) are tumor suppressors that normally participatein DNA repair and maintenance of genomic integrity.
· Mutations in BRCA1 (on chromosome 17q21) and BRCA2 (on chromosome 13q12) are responsible for most breast cancers.
· - Breast carcinomas associated with BRCA1 mutations are poorly differentiated, have medullary characteristics and are biologically very similar to RE-negative/HER2-negative carcinomas.
· - Breast carcinomas associated with BRCA2 mutations are poorly differentiated, however they are more ER. positive than BRCA1 carcinomas.
· Other possible mutations:
· TP53 (Li Fraumeni syndrome);
· CHEK2;
· PTEN (Cowden syndrome);
· STK11 (Peutz-Jeghers syndrome):
· TMJ (ataxia telangiectasia);
· The ATM gene detects DNA mutations and with p53 and CHEK2 induces cell cycle arrest. BRCA1, BRCA2 CHEK2 have important roles in double stranded DNA repair.
SPORADIC BREAST CANCER
· Estrogen works as a breast cancer stimulator.
· - Hormonal exposure stimulates breast growth during puberty, menstrual cycles and pregnancy, thereby increasing the number of cells with the potential to cause cancer
The stem cells remaining in the breast tissue are, in theory, the cells that give rise to breast cancer. There are three genetic pathways in this carcinogenic process:
1. Pathway of ER-positive carcinomas;
2. Pathway of HER2-positive carcinomas;
3. Pathway of ER-negative carcinomas;
Pathway of ER positive carcinomas
Estrogen receptor positive and HER2-negative.
· It is the most common subtype of breast cancer in individuals who have inherited germline mutations in BRCA2.
· It has activation mutations in PIK3CA (phosphoinositide 3 kinase-P13K decoding gene).
· Alteration also present in flat epithelial atypia and atypical ductal hyperplasia (precursor lesions of this subtype of breast cancer).
This carcinoma is called "luminal" because it is similar to normal breast luminal cells in terms of mRNA expression, which is dominated by estrogen-regulated genes.
Pathway of HER2-positive carcinomas
· It originates from an amplification of the HER2 genes.
· They can be both RE-positive and RE-negative.
· It is the most common subtype of breast cancer in patients with mutations in TP53 (Li-Fraumeni syndrome).
· Possible precursor lesion: atypical apocrine adenosis.
· They have distinct gene expression driven by proliferation-related genes regulated by HER2 tyrosine kinase receptors.
Pathway of RE-negative carcinomas
· Estrogen receptor negative and HER2 negative
· It originates in a distinct pathway that is independent of ER- or HER2-mediated changes.
· Possible precursor lesions are unknown.
· Most common tumor type in a patient with BRCA1 mutations.
· It occurs a lot in African-American women.
· Sporadic tumors of this type have a mutation in TP53 (loss of function).
PATHOGENESIS IN SUMMARY:
· The most common mutation responsible for guiding the development of neoplasia involves the proto-oncogenes PIK3CA, HER2, MYC and CCND1, and the tumor suppressor genes TP53 and BRCA1 and BRCA2 (hereditary carcinomas).
· Cancer originates in areas of greater density, so the concentration of fibrous stroma is a risk marker.
· The stroma is a mixture of fibroblasts, blood vessels, lymphatics, inflammatory cells and extracellular matrix.
NATURAL HISTORY OF CA MAMA:
· Breast carcinoma goes through an in situ phase, where the basement membrane is preserved, progressing to the rupture of this membrane, progressing to the invasive form.
· Invasive carcinoma can remain for a variable time as a local disease (limited to the breast) or evolve with regional propagation and distant dissemination, which occurs mainly through the lymphatic route and more rarely through the hematogenous route.
· Once inside the lymphatics, the tumor can reach the sentinel lymph node and from there, the entire ganglionic chain, especially those in the axillary chain.
· CM growth time is related to the degree of histological differentiation, exposure to hormonal stimuli, immune response and nutritional status, being slow most of the time and fast, eventually, slow.
· The average cell doubling period isapproximately 100 days.
· Metastatic involvement of lungs, liver and bones occurs in more than 85% of BC with distant metastases
	
CLINIC
	
1 – Asymmetry 2 – Lump 3 – Inverted nipple 4 – Orange peel skin 5 – Internal nodule 6 – Growing vein 7 – Holes 8 – Unknown fluid 9 – Redness or burning 10 – Induration 11 – Furrows 12 – Skin erosion
	
NOTE: MALE BREAST
	It consists of a rudimentary ductal and mammillary pattern, without lobular formation.
• GYNECOMASTIA Male breast enlargement (uni or bilateral), with dense collagenous connective tissue and papillary epithelium undergoing hyperplasia, commonly resulting from hormonal imbalance, with estrogens being the main hormones that trigger the pathology.
• CARCINOMA Occurs in less than 1% of cases. It has similar risk factors to females (affected 1st degree family member, decreased testicular function - Klinefelter Syndrome, obesity, advanced age, exposure to exogenous estrogens, previous radiotherapy). In men, the most common breast carcinoma is papillary, usually presenting as a palpable subareolar mass of 2 to 3 cm in size (since the male breast epithelium is limited) and may, more frequently, invade thoracic structures and ulcerate the skin. Prognosis, metastases and treatments are similar for men and women with the same stages of cancer.
	
TRACKING
	· should be performed with women over 40 years old
· annual mammogram and physical exam
	According to INCA, screening should be restricted to the age group between 50 and 69 years, through mammography every 2 years.
The association of mammography and ultrasound in cases of dense breasts, or magnetic resonance imaging, in those with high familial risk for breast cancer, is accepted.
· MAMMOGRAPHY
· better identifies breast lesions after menopause
· before
· denser breasts
· sensitivity reduces
· more false negatives and false positives
· unnecessary exposure to radiation and the need for further tests
	· Breast self-examination is NOT recommendedas a technique to be taught to women for breast cancer screening
· Low effectivenessand possible harm associated with this practice
· Does not reduce mortality
· Women should be encouraged to know what is normal in their breasts and to notice changes suspicious of cancer, through occasional observation and palpation of their breasts, in everyday situations, without periodicity and standardized technique, as was the case with the self-examination method. .
· USG
· Complementary screening → always after mammography
· Reserved for specific groups of women → those at high risk or with dense breasts
· BAD PROGNOSIS:
· When the tumor reaches 2 cm or more → ↓ the chances and survival time.
· When cancer cells spread through the lymphatic system to the axillary lymph nodes
· If lymph nodes are not already involved, the chances of a 5-year survival are approximately 82%; however, if four lymph nodes or more are involved, the chances of survival drop to 21%
	
DIAGNOSIS
	
· THE FINAL DIAGNOSIS IS MADE WITH ANATOMOPATHOLOGICAL! (biopsy)
· The choice of method will depend on: radiological classification, type, location of the lesion, breast size
	
STAGING
	· BI-RADS:Breast Imaging Reporting and Data System
· Standardization of breast radiological exams proposed by the American College of Radiology
· Rating from 0-6:
· BI-RADS 0:inconclusive
1. Supplement with another exam, incidence or magnification
1. Radiological examination → breast USG
. BI-RADS 1:no changes
2. Follow screening recommendation every 2 years
. BI-RADS 2:benign lesion
3. Benign radiological findings → simple cysts, breast implants, typically benign calcifications
3. Screening recommendation every 2 years
. BI-RADS 3:very likely benign
4. Chance of malignancy is < than 2%
4. Ex: grouped and punctiform microcalcifications, focal asymmetry, non-palpable solid nodules with characteristics of benignity (regular, without acoustic shadow, horizontal) and grouped microcysts
4. Recommendationis to repeat the exam in 6 months → for 2 years
. BI-RADS 4:Malignancy risk variable from 2 to 95%, with an average of 40%
5. They are microcalcifications and irregular nodules
5. Recommendation for anatomopathological study
5. It is subdivided into 4A, 4B and 4C
. BI-RADS 5:highly suspicious
6. Risk > 95% of malignancy: spiculated nodules, pleomorphic or ductal microcalcifications
6. Recommendation for anatomopathological study
. BI-RADS 6:Already diagnosed with cancer
7. Around 40% of carcinomas without palpable nodules present in the form of clustered microcalcifications
	
TREATMENT
TREATMENT
TREATMENT
	· Varies according to the stage of the disease, its biological characteristics, age, menopausal status, comorbidity and preferences
· Prognosis: depends on the extent of the disease (staging) + characteristics of the tumor
· It begins with surgical removal of tumors and biopsy of lymph nodes.
· Surgical treatment requires the removal of part or all of the affected lymphocytes.
· tto local: surgery and radiotherapy (in addition to breast reconstruction)
· systemic treatment: chemotherapy, hormonal treatments and biological therapy
TTO LOCATION:
Surgery:
· Conservative:Assess the tumor/breast ratio (ideally <20% of the breast)
· Segmentectomy/Sectorectomy or Quadrantectomy
· obs: Post-operative radiotherapy is mandatory → CI remains in cases where there is no access to radiotherapy
· Radical- Mastectomy:
sentinel lymph node
· Infiltrating tumor = Evaluate Lymph Node:How much ↑ tumor = + chances of axillary involvement
· Intraoperatively: blue or technetium dye is applied: perform pathological analysis of 1Olymph node draining the tumor region
· Negative = avoids radical axillary dissection
· Surgery complications:
· Lymphedema
· Disorders in arm movement
Radiotherapy
· conservative surgery
· Thou>4cm
· If QT is indicated, the radio should be after
SYSTEMIC TTO:
Chemotherapy:
· Systemic control:
· Thou>1 cm;
· Lymph node +;
· HER 2 expression;
· Hormone receptor -.
→ Neoadjuvant CT: for locally advanced tumors → intention of ↓ the tumor
Target Directed Therapy:
· Target: estrogen receptor → UseTamoxifen(young) or aromatase inhibitors (postmenopausal)
· TRASTUZUMAB:standard tto → both in adjuvance and tto of 1Oline
· Tumors with overexpression of HER-2
· Is associated with Cardiotoxicity → particularly when combined with anthracyclines (red chemotherapy)
· Trastuzumab and angiogenesis inhibitors:
· Effect appears around 8-16 weeks
· CI → no direct relationship with the dose
· Reversible damage in most cases → irreversible when associated with anthracycline
· Additional risk factors:
· CV disease
· genetic predisposition
· Prior use of anthracyclines
· Myocardial ischemia, Thromboembolism, Hypertension
· ANTHRACYCLINES (doxorubicin):
· CI → direct relationship with dose (50% structural change)
· 400mg (5%), 550mg (16%) and 55mg (26%)
· irreversible damage
· Early (up to 1 year later)
· Late (after 1 year)
· Additional risk factors:
· CV disease
· genetic predisposition
· High blood pressure and diabetes
· Obesity, ↓ weight
· Radiotherapy
· Concomitant chemotherapy
· Extremes of age, cumulative dose, bolus
· Prevention of Cardiotoxicity:
· Decreased Cardiotoxic Potency
· Cardioprotective medication
2. B-blockers
2. Dexrazoxane
2. ACE
2. BRA
· ANTIMETABOLITES (5-fluorouracil-5-fu and capecitabine):
· Cardiotoxicity ↓ common → but potentially lethal
· Incidence: 1.6 to 18% (5-FU) and 3 to 9% (Capecitabine)
· Predominant clinical presentation: angina with electrocardiographic alteration
· Rare events: infarction, serious arrhythmias, HF, cardiogenic shock, Takotsubo and death
· Incidence: > with 5-FU in ↑ doses and continuous infusion
· Chemotherapy: Red X White
· Red: formed by a class of drugs called anthracyclines, which have reddish tones
· Fatigue occurs → + strong and + common than white
· Reddish coloration in the urine → when medicine leaves the body
· Anthracyclines: more acidic and tend to be aggressive to peripheral veins → such as those in the crease of the arm and the back of the hand
· White:formed by several classes of drugs that do not have any color, such as:
· Cyclophosphamide, Taxanes, Gemcitabine and Vinorelbine
· milder