Breast cancer: Diagnosis and complex treatment. Ibolya Czegle MD PhD Semmelweis University 3rd Department of Internal Medicine

Transcription

1 Breast cancer: Diagnosis and complex treatment Ibolya Czegle MD PhD Semmelweis University 3rd Department of Internal Medicine

2 Epidemiology Worldwide, breast cancer is the most frequently diagnosed life-threatening cancer in women and the leading cause of cancer death in women. In the United States, breast cancer accounts for 29% of all cancers in women and is second only to lung cancer as a cause of cancer deaths.

3 Epidemiology In 2008, the estimated age-adjusted annual incidence of breast cancer in Europe (40 countries) was 88.4/ and the mortality 24.3/ The incidence increased after the introduction of mammography screening and continues to do so with the aging of the population..

4 Risk factors Genetic predisposition: BRCA1/2 mutations Exposure to estrogens (endogenous and exogenous) Ionising radiation, Low parity History of atypical hyperplasia Western-style diet Obesity Consumption of alcohol OAC

5 Screening Self examination Physical examination Mammography screening: 20% relative breast cancer mortality reduction between yrs MRI screening: BRCA1/2 mutation carrying population

6 Anatomy The breasts of an adult woman are milk-producing glands on the front of the chest wall. They rest on the pectoralis major and are supported by and attached to the front of the chest wall on either side of the sternum by ligaments. Each breast contains lobes arranged in a circular fashion. The fat that covers the lobes gives the breast its size and shape. Each lobe comprises many lobules, at the end of which are glands that produce milk in response to hormones

7 History and symptoms Many early breast carcinomas are asymptomatic, particularly if they were discovered during a breast-screening program. Most common: lump Larger tumors may present as a painless mass. Pain or discomfort is not usually a symptom of breast cancer; only 5% of patients with a malignant mass present with breast pain.

8 Physical examination If the patient has not noticed a lump, then signs and symptoms indicating the possible presence of breast cancer may include the following: Change in breast size or shape Skin dimpling or skin changes (eg, thickening, swelling, or redness) Recent nipple inversion or skin change or other nipple abnormalities (eg, ulceration, retraction, or spontaneous bloody discharge) Nipple discharge, particularly if bloodstained Axillary lump

9 Physical examination To detect subtle changes in breast contour and skin tethering, the examination must include an assessment of the breasts with the patient upright with arms raised. The following findings should raise concern: Lump or contour change Skin tethering Nipple inversion Dilated veins Ulceration Mammary Paget disease Edema or peau d orange

10

11

12

13 Physical examination The nature of palpable lumps is often difficult to determine clinically, but the following features should raise concern: Hardness Irregularity Focal nodularity Asymmetry with the other breast Fixation to skin or muscle (assess fixation to muscle by moving the lump in the line of the pectoral muscle fibers with the patient bracing her arms against her hips)

14 Diagnostic evaluation Imaging techniques: Breast ultrasound Mammography MRI Histology: Aspiration cytology Core biopsy

15

16 Histology Types: Invasive ductal carcinoma=idc Invasive lobular carcinoma=ilc Ductal carcinoma in situ (DCIS) Lobular carcinoma in situ (LCIS) Medullary carcinoma Papillary carcinoma Mucinous carcinoma Paget s disease

17

18 Histology Grade 1-4 Grade (1: good, 2: average, 3: poor, 4: undifferentiated) Biomarkers for planning targeted therapies= immunohistochemistry

19 Immunohistochemistry ER (oestrogen receptor) PR (progesterone receptor) HER2 receptor

20

21 TNM Classification

22 Staging T and N status: mammography, breast US, MRI M status: - CT scan - MRI - PET scan

23 Treatment Surgery Chemotherapy Radiation therapy Hormonal therapies Biological (targeted) therapies

24 Surgery Operation types: Matectomy: try to avoid if possible (cosmetical outcome, psychological factors) Breast conservation techniques: - Sectorectomy (lumpectomy, quadrantectomy), nipple sparing mastectomy - T1-2 tumors or T3 after successful neoadjuvant treatment

25 Surgery Axilla: - ABD=Axillary block dissection - SLNB= sentinel lymph node biopsy

26

27

28

29 Surgery Primary reconstruction: immediately after mastectomy, in the same operation - Implant - Latissimus dorsi flap reconstruction - Abdominal flap reconstruction - TRAM flap reconstruction Pedicle flap: vasculature from the original site Delayed reconstruction: elective time, 2-3 years after mastectomy

30

31

32

33

34 Oncoteam/Tumor board Multidisclipinar patient management Optimally before and after surgery Histology: type, grade, prognostic factors (ER, PR, HER2 status), proliferation markers (Ki-67), TNM: pathological, clinical Judgement: chemotherapy, hormonal therapy, targeted therapies, radiotherapy

35 HER2 status Important prognostic factor for planning treatments Immunohistochemistry FISH=fluorescent in situ hybridization

36 Performing FISH examination

37 HER2 FISH

38 Chemotherapy Neoadjuvant Adjuvant Palliative

39 Chemotherapy Neoadjuvant chemotherapy Indications: T2-3 tumor, avoid mastectomy Drugs: anthracyclines, cyclophosphamid, 5-FU, taxanes Protocols: 6xFEC, 3xFEC+3xTXT, 6xTAC FEC= 5-FU+epirubicin+cyclophosphamid TXT=docetaxel TAC=docetaxel+adriamycin+cyclophosphamid Re-staging after 3 cycles Tumor labeling with metal clips if necessary

40

41 Chemotherapy Adjuvant chemotherapy Indications: T2-3 tumor, node positivity, high proliferation rate, HER2 positivity Drugs: anthracyclines, cyclophosphamid, taxanes, 5-FU Protocols (6 cycles): AC= adriamycin+ccylophosphamid EC= epirubicin+cyclophosphamid TAC=docetaxel+adriamycin+cyclophosphamid FEC= 5-FU+epirubicin+cyclophosphamid

42 Chemotherapy Palliative setting: for metastatic patient Treatment response: re-staging every 2-3 months (CT) Drugs: anthracyclines, cyclophosphamid, 5-FU, taxanes, vinca alkaloids, gemcitabine Combination with biological therapies

43 Radiation therapy Teletherapy: external radiation source Breast, tumor bed, axilla, affected lymph node regions Indications: high risk for locoregional recurrence (after sectorectomy always!!!) Goal: prevention of locoregional recurrence

44 Hormonal therapy Adjuvant, neoadjuvant, metastatic (only absence of life-threatening visceral mets!) Antiestrogens (Selective Estrogen Receptor Modulators=SERM): tamoxifen Aromatase inhibitors (AIs): anastrozol, letrozol, exemestan- postmenopausal patients only GnRH analogs: goserelin

45 Biological (targeted) therapies Anti- HER2 agents Angiogenesis inhibitors PARP (poly-adp-ribose-polymerase) inhibitors

46 Biological (targeted) therapies Anti-HER2 agents: Monoclonal antibodies : trastuzumab small molecule TKI: lapatinib HER2 dimerization inhibitor: pertuzumab ADC (antibody-drug conjugate) molecule: TDM1

47

48 ADC molecules Uptake of cytostatic drugs with antibodies through overexpressed cancer cell receptors Higher concentration of cyctostatic drug in the cancer cell Lower concentration in healthy tissues Better side effect profile

49 TDM1 Trastuzumab: antibody DM1(maytansine): cytostatic drug MCC: binding molecule

50 Anti-HER2 therapies Adjuvant: trastuzumab Neoadjuvant: trastuzumab Palliative: - Trastuzumab: in combination with docetaxel - Pertuzumab - TDM1: monotherapy - Lapatinib: in combination with capecitabine

51 Angiogenesis inhibition In metastatic setting Drug: bevacizumab- in combination with paclitaxel

52 Angiogenesis inhibition

53 PARP Inhibition BRCA1/2 mutation carriers Drug: veliparib, olaparib

54 BRCA in breast cancer Tumor suppressor genes 17q12-21: BRCA1, 13q12-13: BRCA2 Familial susceptibility for breast cancer: less than 25% of cases BRCA associated breast cancer: 10%

55 BRCA Testing Referral Three or more breast/ovarian cancer cases, at least one younger than 50 yrs Two breast cancer cases <40 years; Male breast cancer and ovarian cancer or early onset female breast cancer; Ashkenazi Jew with breast cancer of <60 years; Young onset bilateral breast cancer; Breast and ovarian cancer in the same patient

56 BRCA-Risk reduction Surveillance: monthly self-examinations, clinical breast examinations twice a year and yearly mammograms and magnetic resonance imaging (MRI) of breasts starting at age Prophylactic bilateral mastectomy Prophylactic bilateral salpingooophorectomy

57 BRCA positive breast cancer The overall prognosis of breast cancer in BRCA carriers is similar to sporadic breast cancers BRCA deficiency seems to be predictive of chemosensitivity, especially to DNA-damaging agents (eg. Platinum derivates) Poly (ADP-ribose) polymerase (PARP) inhibitors are being developed as single therapeutic agents for BRCA breast and ovarian cancer patients. These drugs inhibit a pathway of DNA single-strand break repair and lead to apoptosis in BRCA-deficient cancer cells, which already have a deficiency in homologous recombination repair.

58 Source