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which is a structural and functional unit of the breast. In essence, one terminal duct (arrow) of the breast duct system gives rise to a collection of smaller ductules (arrowhead) called a "Lobule" which 'produces' milk to be discharged through the duct system. Most cancers are thought to arise from cells of these TDLUs.

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Terminal duct lobular unit

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Neoplastic cells-limited within ducts, lubules by BM

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Breast carcinoma-In situ

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penetrated through the BM into stroma

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Breast carcinoma-invasive

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BRCA 1/2 P53 CHEK2

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Most common genes implicated in breast carcinoma

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FNA: smaller needle, isolated cells, not useful for finding additional fetures Core Biopsy recommended

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Breast Biopsy

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ER, PR, Her2, Ki67 proliferative index Prognosis: tells how well the patient will do Predictive: how well the tumor will respond to certain treatments

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Histological studies for BC

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Big magnet, gadallenium for tracer Anything that has enhanced blood flow, has more gadallenium in it, and appears brighter on MRI (enhancing or lighting up) Important new tool for imaging the breast High sensitivity (low specificity) Detection and characterization of otherwise-occult breast carcinoma

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Breast MRI

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If mastectomy is chosen, then no more treatment necessary, if lumpectomy is chosen then it should be followed by breast irradiation. Then no difference in survival; ( although there appears to be a higher risk of reoccurrence) Irradiation bear a small change of sarcoma (angiosacroma 5-10 years down the road)

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lympectomy vs. masectomy

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Wire gets slipped in, make incision, take out the wire with the lump around it

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wire localization during lympectomy

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1. Inject around area of tumor with blue dye, radioactivity, or both 2. Track the lymphatic drainage of the tumor The purpose of the sentinel lymph node biopsy is to determine if the FIRST (sentinel) lymph node in the draining chain has cancer. IF the first lymph node is negative, you can assume the other lymph nodes are negative and don't need an axillary dissection.

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sentinel lymph node biopsy

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whole breast irradiation The purpose of the radiation is to kill any residual neoplasm that wasn't removed at surgery. Spill of tumor during surgery Tumor does not grow in a tight little ball, there are tumor cells throughout; if you get radiation, it decreases recurrence

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to complete local regional therapy of BC

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Anti-estrogen therapy

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systemic therapy for ER+/PR+/HER-

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BC staging

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1. Tubule formation (if there is a lot, its like a breast tissue) 2. Mitotic figures (dividing more rapidly?) 3. Nuclear grade, nuclear: cytoplasmic ratio Stage III: Key here: no gland formation, solid sheet of cancer cells, giant nuclei, high mitotic rate = high grade tumor does not at all look like normal breast tissue

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Breast grading

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Her2 receptors

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Standard of care for locally advanced breast cancer Potential for improved surgical outcome Allows "in vivo" test of tumor responsiveness to therapy Exposes micrometastatic tumor cells to chemotherapy at an earlier time point (? better chance for cure) **prior workup should include: Breast MRI (if poorly visualized on mammogram and ultrasound Bone scan CT of the chest, abdomen and pelvis This screens for distant metastasis!!!! Stage 3 versus stage 4 If patient also has headaches, then a Brain scan is also performed The key is that stage 4 brearst cancer can not be cured, however, for stage 3 there is a chance for a cure!!!!!

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Preoperative (Neoadjuvant) Chemotherapy

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This patient has a bad tumor with a high proliferative rate == you will kill proliferating cells with chemotherapy, but need also anti-Her2 (Trastuzumab (Herceptin)) to potentially also target non-proliferating tumor cells and to aid killing of proliferating cell. -mastectomy and auxillary node dissection, and then radiation

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treatment for BC with high proliferative rate and HER2+

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BRCA1, BRCA2, (account for up to 10% of breast cancer types, 25-50% of hereditary breast cancer) PALB2 Next-Gen sequencing done for several genes in hereditary cancer panels (BRCA1/2) Oncotype testing on RNA for RECURRENCE (Breast cancer assay and Mammaprint, i.e. ); Oncotype DX helps predict the chance of metastasis for breast cancers

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Types of genetic testing

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-immunohistochemical staining assay

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Types of hormone or receptor testing

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surgery to remove one or more lumps

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lumpectomy

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remove one or more breasts

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mastectomy

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occur after the primary treatment They may include radiation treatment, chemotherapy, and targeted treatments that are based on the specific characteristics of a particular breast cancer.

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Adjuvant treatments

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done before the primary treatment Neoadjuvant chemo- or targeted therapy may be attempted before surgery to promote shrinkage of a large breast tumor can also give info about tumor responsiveness to drug

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Neoadjuvant treatments

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Higher prevalence of BRCA 1 and 2 in Ashkenazi Jewish ethnicity and others

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BRCA mutations are associated with different ethnic groups

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If you have ER+ breast cancer, your cancer cells grow in the presence of the hormone estrogen By blocking estrogen, doctors can improve the likelihood of controlling ER+ breast cancers. ER+ breast cancers have the most favorable prognosis of all subtypes typically responds to hormone therapy

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Estrogen receptor-positive (ER+) breast cancer

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The Oncotype DX test is a genomic test that analyzes the activity of a group of genes that can affect how a cancer is likely to behave and respond to treatment Normalized for RNA content using expression of 5 control genes Expression of 16 cancer-related genes analyzed obtain recurrence score

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OncotypeDx Breast Cancer Assay

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breast cancer cells that have hormone receptors. These receptors are special proteins that the hormones estrogen and progesterone bind to. Breast cancer cells that are HR positive depend on estrogen and progesterone to grow. Hormonal therapy blocks the receptors or reduces the amount of hormones that can get into the receptors. As a result, the cancer cells shrink or die.

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HR+

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human epidermal growth factor receptor 2 HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. Amplification or overexpression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. amplification=>2 HER2 genes/nucleus

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HER2

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Elevated HER2 activity can reduce the growth factor dependence of cells -HER2 does NOT bind a ligand itself, but dimerizes with HER1, HER3, or HER4 (no HER2 dimers) and initiates MAPK pathway -HER3 in a dimer activates prosurvival PI3K signaling -HER2/HER3 heterodimers activate both MAPK and PI3K pathways Consequences Prolonged stimulation of signaling pathways (e.g. MAPK, PI3K) Uncontrolled growth of breast cancer cells Inhibition of apoptosis Resistance to chemotherapy, radiotherapy, and other targeted therapies

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Consequences of increased HER2 activity

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Mediates antibody dependent cytotoxicity (flags HER2+ cancer cell for destruction by immune system) Suppresses HER2 signaling causing cell cycle arrest and apoptosis Herceptin responders often build up RESISTANCE within a year or two Can cause reduced heart function and congestive heart failure

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Herceptin (Trastuzumab)

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normal proteins involved in multiple cellular functions including repair of double-strand breaks in DNA BRCA1 gene is sometimes hypermethylated, which inhibits its expression

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BRCA 1 (Breast cancer 1, early onset) and BRCA 2

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includes RNA Pol II and histone deacetylases. BRCA 1 and BRCA 2 interact with a wide range of proteins involved in transcription, chromosome maintenance, DNA repair and cell cycle control

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BRCA 1-associated genome surveillance complex" (BASC)

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-BC diagnosed before age 50 in family member -Cancer in both breasts in same woman in family -BC and ovarian cancer in same woman or in same family -Multiple BCs in same family -2 or more BRCA-related cancers in single family member -Cases of male BC -Ashkenazi Jewish ethnicity

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Family factors associated with increased risk of harmful BRCA mutation in an individual

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NF1 is a GTPase-activating protein (GAP) aiding hydrolysis of GTP in MAPK signaling NF1 defect present in many other cancers, notably neurofibromatosis NF1 mutants usually cause hyperactivation of MAPK pathway

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NF1 (Neurofibromin 1)

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The ATM gene provides instructions for making a protein that is located primarily in the nucleus of cells, where it helps control the rate at which cells grow and divide. This protein also plays an important role in the normal development and activity of several body systems, including the nervous system and the immune system. Additionally, the ATM protein assists cells in recognizing damaged or broken DNA strands. disease association: ataxia telangiectasia

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ATM

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checkpoint kinase 2 The CHEK2 gene provides instructions for making a protein called checkpoint kinase 2 (CHK2). This protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing too rapidly or in an uncontrolled way. The CHK2 protein is activated when DNA becomes damaged or when DNA strands break.

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Chek2

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partner and localizer of BRCA2 it interacts with BRCA2 to fix broken DNA

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PALB2

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Chek2 mutant, ATM mutant, PALB2, BRCA 1/2

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Genes associated with inherited breast cancer

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supraclavicular intraclavicular axillary (75%) internal mammary

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axillary and other draining lymph nodes

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fine needle aspiration biopsy non-surgical, distinguish between cyst and non-cyst

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FNA

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biopsy like FNA, uses larger needle to remove sample

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core

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entire lump removed (lumpectomy)

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open excision

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radioisotope to trace lymph node drainage before mastectomy If negative, conclude that cancer has not spread LN-/LN+ (lymph node affected with cancer) status affects how aggressive the breast cancer will be treated

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sentinel lymph node biopsy (SLNB)

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- Mass detected in breast - Calcifications seen in Xray - Architectural distortions (MRI)

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why perform biopsy?

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Radioisotope injected several hours before surgery. Location of probe located visually (dye) and with Geiger counter (99mTc) Sentinel Lymph Nodes (SLNs) and tumor removed

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Sentinel Node Lymphoscintigraphy

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Non-invasive breast cancer with cells only in the ducts, not in breast tissue, with low risk of being lymph node positive

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Ductal carcinoma in situ (DCIS)

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Cancer cells escaped ducts or lobules and invaded breast tissue; higher risk of lymph node positive than with DCIS (ductal-IDC, lobular-ILC)

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Invasive (inflitrating) carcinoma (IDC or ILC)

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-Uncommon (1-3% of all breast cancers) -Usually no lump, but skin red, pitted, or feel warm -Breast may be enlarged, hard, tender or itchy -May be unremarkable on mammogram

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Inflammatory breast cancer (IBC)

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actin-rich protrusions of the plasma membrane that are associated with degradation of the extracellular matrix in cancer invasiveness and metastasis. how cancer cells escape primary tumor

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Invadopodia

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are a group of enzymes that in concert are responsible for the degradation of most extracellular matrix proteins during organogenesis, growth and normal tissue turnover. how cancer cells escape primary tumor

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Matrix metalloproteinases (MMPs)

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ER+: cells grow in response to the hormone estrogen PR+: cells grow in response to progesterone HER2: human epidermal growth factor receptor 2; HER2 proteins are receptors on breast cells. Normally, HER2 receptors help control how a healthy breast cell grows, divides, and repairs itself

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receptors and breast cancer

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Invasive vs in situ disease Presence of distant metastasis (Stage IV) Presence of lymph node metastasis (*most important factor in cases without distant metastases) Size (cutoffs 5 cm) Inflammatory, chest wall or skin invasion (Stage III) used to assign stage

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major prognostic factors

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Nottingham grade Histologic type Hormone receptor status HER2 status Proliferative rate Lymphovascular invasion predictive of response to therapies

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minor prognostic factors

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Score of 1-3 assigned in 3 categories: Tubule formation Mitotic count Nuclear pleomorphism (how much variation there is in nuclear size, shape and staining properties)

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Nottingham grade

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Classification based on: -Extent of primary tumor -Presence in lymph nodes -State of metastasis to other organs (e.g. brain, bone, lung, liver, other)

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Traditional Breast Cancer Staging (TNM)

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This parameter assesses what percent of the tumor forms normal duct structures. In cancer, there is a breakdown of the mechanisms that cells use to attach to each other and communicate with each other, to form tissues such as ducts, so the tissue structures become less orderly.

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Tubular formation

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This parameter assesses whether the cell nuclei are uniform like those in normal breast duct epithelial cells, or whether they are larger, darker, or irregular (pleomorphic). In cancer, the mechanisms that control genes and chromosomes in the nucleus break down, and irregular nuclei and pleomorphic changes are signs of abnormal cell reproduction.

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Nuclear Pleomorphism

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1. luminal A 2. Luminal B 3. Basal-like, Triple negative (TN) (15%) 4. HR2 enriched others: Normal breast-like, claudin-low

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4 main molecular subtypes of breast cancer

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Typically are larger and a higher TNM grade High rate of recurrence High rate of distant metastasis Not susceptible to therapies targeted against cancer cells with estrogen, progesterone, or HER2 receptors

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Triple Negative Breast Cancers (TNBC)

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chemotherapy PARP inhibitors

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Treatment of Triple Negative Breast Cancers (TNBC)

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Poly (ADP-ribose) polymerase catalyzes ribosyltransferase addition of ADP-ribose units Under normal conditions, PARP activity is associated with converting chromatin to a transcriptionally active unit PARP is involved in several cellular processes -Transcriptional activation via chromatin opening -Programmed cell death (Apoptosis) -DNA repair PARP deficiency Causes defect in DNA repair and other consequences

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PARP

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PARP inhibitors prevent base excision repair and cause death in cells with BRCA defects (which would normally repair dsDNA breaks) BRCA-deficient cancer cells don't repair the multiple dsDNA breaks observed, and cell dies (PARP catalytic inhibitors) DNA replication blocked by trapped PARP; cell dies (PARP poison)

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PARP inhibitors

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nuclear protein present in actively dividing cells; marker of proliferation

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Ki67

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heterodimer of cytokeratins 5 and 6; subunits of keratin-containing intermediate filaments found in the basal/myoepithelial cells in the breast Primary tumors and metastases of a given carcinoma share the same pattern of cytokeratins, that distinguishes them from other types of carcinomas

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Cytokeratin 5/6

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are a family of proteins that are the most important components of the tight junctions, where they establish the paracellular barrier that controls the flow of molecules in the intercellular space between the cells of an epithelium. cellular tight-junction proteins; absence of claudins is characteristic of epithelial-to-mesenchymal transition (EMT) leading to cancer development

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Claudin

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is a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells; these are multipotent stromal cells that can differentiate into a variety of cell types.

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epithelial-mesenchymal transition (EMT)

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non-coding RNAs regulating gene expression post-transcriptionally by binding to complementary sequence and causing degradation or inhibition of translation of that mRNA potential: stimulate miRNAs binding to oncogene mRNAs or inhibit miRNA binding to tumor suppressor mRNAs

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miRNAs

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Delivery of 1-5 high-potent biological doses of radiation to the tumor Multiple radiation beam angles used to deliver the radiation A sharp dose gradient outside of tumor protects healthy tissue: minimize dose to any individual region of tissue outside of tumor; reduced tissue damage and reduced incidence of radiation burns

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Stereotactic Body Radiation Therapy (SBRT)

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Radioactive seeds (commonly iridium) fed through flexible, plastic catheter(s) into lumpectomy cavity to kill any tumor cells

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Breast Brachytherapy

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Doxorubicin (Adriamycin) and epirubicin (Ellence) Adriamycin replaced earlier treatments with cyclophosphamide, methotrexate, and 5-FU Most effective for HER2+ breast cancer Side effects Short term: nausea, hair loss Long term: heart damage (1-2%) and leukemia (;1%)

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Anthracycline Chemotherapy

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A taxane that binds beta-tubulin and stabilizes mitotic spindles, thus inhibiting required tubulin depolymerization cycle Cyclophosphamide: "Nitrogen mustard alkylating agent" adds group (CnH2n+1) to guanine at position 7; causes intra- and interstrand DNA cross-links

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Taxotere (docetaxel) Chemotherapy

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-Alter estrogen receptor activity (selective estrogen receptor modulator, SERM,) e.g. Tamoxifen -Inhibit estrogen synthesis (Aromatase Inhibitor, AI) -Selective estrogen receptor down-regulator (SEDR) e.g.fulvestrant (Faslodex); used for metastatic ER+ BC if get disease progression post anti-estrogen therapy -Interfere with hypothalamopituitary-gonadal regulatory axis to suppress estrogen formation (ovarian ablation/suppression)

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Targeting of Estrogen Response in Breast Cancer

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SERM, e.g. Tamoxifen, competes with estrogen for binding to receptor Tamoxifen blocks binding of co-activators to receptor, so inhibits activation of gene expression

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(selective estrogen receptor modulator, SERM,) e.g. Tamoxifen

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1. Estrogen receptor (ER) interacts with estradiol (E2) 2. Hormone/receptor complex binds estrogen DNA response elements (ERE) 3. Genes with ERE are transcribed

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Normal Estrogen Receptor Binding to Estradiol (E2) Ligand

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Cytochrome P450 enzymes are involved in metabolizing Tamoxifen 4 phenotypes of CYP2D6: UM = Ultrarapid Metabolizer EM = Extensive Metabolizer IM = Intermediate Metabolizer PM = Poor Metabolizer Women with CYP2D6 *4/*4 genotype tend to have poor-metabolizer status for Tamoxifen (less ability to make metabolites (endoxifen) that block ER binding?)

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CYP2D6

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Tamoxifen used in treatment of ER+ breast cancer Tamoxifen converted to various metabolites that have a greater affinity for the ER 4-hydroxytamoxifen 4-hydroxy-N-desmethyl tamoxifen ("Endoxifen") Cytochrome P450 enzymes are involved in metabolizing Tamoxifen, mainly CYP2D6

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Tamoxifen

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The cytochrome P450 (CYP) family of enzymes is responsible for primary metabolism of many drugs. UM = Ultrarapid Metabolizer* EM = Extensive Metabolizer* IM = Intermediate Metabolizer PM = Poor Metabolizer *good for tamoxifen treatment

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Cytochrome P450 2D6 Testing for Tamoxifen Resistance

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is a cytochrome P450 (CYP19) enzyme catalyzing conversion of androgens to estrogens

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Aromatase

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Aromatase inhibitors block all estrogen production, thus used in postmenopausal women (otherwise instant menopause) Overall aromatase inhibitors do a slightly better job in decreasing recurrence and mortality Aromatase inhibitors work by blocking the enzyme aromatase, which turns the hormone androgen into small amounts of estrogen in the body causes the opposite offect in pre-menopausal women.

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Aromatase Inhibitors (AIs)

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Oophorectomy or Radiation

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Permanent ovarian ablation

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Used in premenopausal women Interferes with hypothalamopituitary-gonadal axis to suppress estrogen formation Give LHRH analog Zoladex (goserelin) which inhibits FSH and LH production from pituitary Consequence is inhibition of ovarian follicle estrogen production

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Temporary ovarian suppression

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