breast cancer Flashcards
what are the main parts of the breast
- Glandular tissue
a. 15-20 lobules, responsible for producing milk
b. Within the lobules there are alveoli – modified sweat glands – that secrete milk.
c. Glandular tissues have receptors for oestrogen & progesterone (released by the ovaries) and prolactin (released by the pituitary gland)
i. Oestrogen and progesterone cause alveolar cells to divide and increase in number, enlarging the lobule
ii. Without hormones, glandular cells undergo apoptosis – after menstruation, alveolar cells die and breast tissue is replaced by fat. - Stroma, containing adipose (fat tissue), is the majority of the breast.
- Lymphatic vessels are found just below the skin covering the breast. They drain lymph – cellular waste & WBCs.
what is breast cancer
Breast cancer is uncontrolled growth of epithelial cells in the breast, forming a tumour. Breast cancer accounted for 15% of all new cancer cases in 2015. 1 in 8 women will be diagnosed with breast cancer during their lifetime. It is the second most common cancer in women.
what are the 2 different subtypes of breast cancer
- Ductal carcinoma in-situ (DCIS) – tumours grow from the wall of the ducts into the lumen. If left untreated, they cross basement membrane. DCIS does invade surrounding tissues.
- Lobular carcinoma in-situ (LCIS) – clusters of tumour cells grown within lobules, causing alveoli to enlarge – ducts are not invaded. LCIS does not invade surrounding tissues.
75% of breast cancers are ductal (spread to surrounding tissues); 17% are lobular (affects milk-producing glands – lobules).
what does it mean when some forms of breast cancers have hormone receptors
Some breast cancers have hormone receptors, allowing them to grow in the presence of hormones.
ER or PR-receptor involvement indicates that the tumour is hormone-dependant tumour, so is more likely to respond to hormonal treatments. The prognosis is more favourable.
what does it mean to have HER2+ breast cancer
HER2 is a transmembrane tyrosine kinase which regulates growth, survival & migration. If a cancer is HER2+, it will be more aggressive, so prognosis is poorer.
- ER-positive & HER2-negative
- HER2-positive & ER-positive/ HER2-positive & ER-negative
- ER-negative & HER2-negative
- ER = oestrogen receptor, PR = progesterone receptor, HER2 = human epidermal growth factor receptor type 2 (aka ErbB2).
what is meant by Carcinoma in situ
Carcinoma in situ is proliferation of cancer cells within the epithelial tissue without invasion of the surrounding tissue. In contrast, invasive carcinoma invades the surrounding tissue. Perineural and/or lymphovascular space invasion is usually considered as part of the histological description of a breast cancer, and when present may be associated with more aggressive disease.
what does DCIS stand for and what does it mean
Ductal carcinoma in situ (DCIS) is the presence of abnormal cells inside a milk duct in the breast. DCIS is considered the earliest form of breast cancer. DCIS is noninvasive, meaning it hasn’t spread out of the milk duct and has a low risk of becoming invasive.
what does LCIS stand for and what does it mean
Lobular carcinoma in situ (LCIS) means that cells inside some of the breast lobules have started to become abnormal. LCIS It is not a cancer. The lobules are glands that make breast milk. The abnormal cells are all contained within the inner lining of the lobules
state whether luminal A is DCIS/LSIC, what hormone receptors are involved, is there any other involvement and what is the treatment plan
DCIS hormone receptors that are involved are : ER + PR + HER2 -
other involvements includes
15% with p53 mutation
and the treatment plan is
Chemo
Radiation
Hormone
state whether luminal B is DCIS/LSIC, what hormone receptors are involved, is there any other involvement and what is the treatment plan
DCIS
hormone receptor involvements includes:
ER +
PR +
HER2 +
other involvements includes
30% with p53 mutation
the treatment plan is
Chemo
Radiation
Hormone
state whether triple negative (basal like) is DCIS/LSIC, what hormone receptors are involved, is there any other involvement and what is the treatment plan
DCIS
hormone receptor involvement includes
ER -
PR -
HER2 -
other involvements
Most with p53 mutation
BRCA 1 involvement
High levels of Ki-67 protein
the treatment plan is
Chemo
Radiation
Biological (Non-HER2 targeted)
state whether HER2 type is DCIS/LSIC, what hormone receptors are involved, is there any other involvement and what is the treatment plan
DCIS
the receptors involved
70% - HER2 +
30% - HER2 -
other involvements
75% with p53 mutation
the treatment plan is
Biological (HER-2 targeted)
what are the risk factors associated with breast cancer
• 60-years-old (as median age of diagnosis is 60-65)
• Oestrogen exposure (e.g. late menopause, use of oral contraceptives and early menarche (first menstruation)
• Genetics
o BRCA 1 & 2 genes play a rule in DNA repair; mutations in these genes confer 80-90% lifetime risk
o TP53 – tumour protein 53
o ERBB2 (HER-2) – receptor tyrosine-protein kinase
• Ethnicity may be classed as a risk factor – more common in white populations
• Obesity, smoking and alcohol use
• Nulliparity – not having children
• Stress (initiates DNA damage)
• Socio-economic status – actually less common if living in deprived areas
Avoiding the above (where possible), breastfeeding and engaging in physical activity are protective – reducing the risk of developing BC.
what does screening entail
Mammography is an X-Ray, offered to all women aged 50-70 every 3 years. 1/100 screened women in the UK have cancer detected through breast screening. Around 8 in 10 of these are invasive cancers. See radiography for further details.
1% of women have breast cancer (and therefore 99% do not).
80% of mammograms detect breast cancer when it is there; 20% of mammograms miss signs of cancer
10% of mammograms detect breast cancer when it’s not there (and therefore 90% correctly return a negative result).
Probability of a 40-50-year old with breast cancer = 7.47%
what are the presentations of breast cancer
BC may present in a variety of ways, including:
Hard, painless lump or swelling
Swelling under armpit (indicates spread to lymph nodes)
Breast immobile
Dimpling, thickening & change in colour (orange) of skin (indicates blockage of lymphatic vessels and involvement of skin)
Retraction/ inversion of the nipple (caused by fibrosis of lactiferous ducts)
Discharge from nipple (paget disease)
how do you diagnose breast cancer
Breast cancer does not cause pain, until it spreads to surrounding tissues.
Median age of diagnosis is 60-65.
• Feeling of a breast lump
• Mammography is also used to confirm diagnosis. About 20% of all cancers of the breast detected by mammographic screening are ductal carcinoma in situ (DCIS).
• Breast biopsy, using methods such as needle aspiration/ ultrasound guided/ stereotactic or open
o Needle biopsy – fluid and tissue from lump is drawn
o Open biopsy (lumpectomy) – all/ part of a lump is removed & tested for malignancy
• Breast MRI helps better identify the breast lump or evaluate an abnormal change on a mammogram
• Breast ultrasound shows whether the lump is solid or fluid-filled
• FBC, LFT, bone profile may help ensure diagnosis, and evaluate invasive nature of cancer
• CT, CAP and bone scan if high risk, to show whether the breast cancer has spread elsewhere
When diagnosed at its earliest stage, around all women with breast cancer will survive their disease for five years or more, compared with 3 in 20 women when the disease is diagnosed at the latest stage.
The following groups are more likely to be unhappy with their care: Long term/multiple conditions other than cancer; ethnic minorities; young patients (16 – 35 years); those attending London Hospitals; LGBT community.
what is the TNM staging
• Tumour size (& extent, of the main tumour)
o T1= <2cm
o T2= 2-5cm
o T3= >5cm
o T4= direct extension to chest wall or skin
• Lymph Nodes (the number of nearby lymph nodes that have cancer)
o N1 = mobile ipsilateral lymph nodes
o N2 = fixed to one another or other structures
o N3 = infraclavicular or ipsilateral internal mammary and axillary nodes
• Metastasis (the development of secondary malignant growths at a distance from a primary site of cancer)
o M0 = no metastasis
o M1= contralateral lymph nodes or any distant metastases
o Mx= Distant metastasis cannot be assessed.
what is meant by the G3 grading pathology
• Grade I (well differentiated/low grade)
o cancer cells look similar to normal cells and grow very slowly
o In low grade invasive ductal carcinoma, glands are still seen
• Grade II (moderately differentiated)
o cancer cells look more abnormal and are slightly faster growing
• Grade III (poorly differentiated/high grade)
o cancer cells look very different from normal cells and tend to grow quickly
o In high grade invasive ductal carcinoma, a sheet of cells is seen, where nuclei are pleomorphic (varies in shape and size); no glands can be seen
what is the TNM and survival rate of stage 1, early stage
T1N0M0, 95%
what is the TNM and survival rate of stage 11A, early stage
T1N1M0
T2N0M0
85%
what is the TNM and survival rate of stage 11B, early stage
T2N1M0
T3N0M0
85%
what is the TNM and survival rate of stage 111A, locally advanced
T3N1M0
T0-3N2M0
55%
what is the TNM and survival rate of stage 111b, locally advanced
T4 Nx M0
55%
what is the TNM and survival rate of stage111c locally advanced
TxN3M0
55%
what is the TNM and survival rate of stage Iv, metastatic
TxNxM1
15%
what is the treatment for breast cancer
• Surgery
o Partial mastectomy for localised tumour
o Total mastectomy (removal of all breast) if tumour has spread. Lymph nodes may be removed if tumour has metastasised.
• Radiation therapy
• Chemotherapy
• Hormonal (biologic) therapy
o If tumour has hormone receptor involvement (ER & HER2), effects/ formation of oestrogen is blocked.
what is meant by the cell cycle
The cell cycle (cell-division cycle) is the process by which a single mother eukaryotic cell gives rise to two identical daughter cells.
Most cells have a finite capacity for division and can become senescent at any time; senescence is the process by which cells irreversibly stop dividing and enter a state of permanent growth arrest without undergoing cell death. Senescent cells sit within the tissue and change the plasticity of the tissue – the longer they sit around, can be promoting a cancer.
what is the cell cycle composed of?
The cell cycle is composed of interphase (G₁, S, and G₂ phases), followed by the mitotic phase (mitosis and cytokinesis), and G₀ phase.
During interphase, the cell grows and makes a copy of its DNA. During the mitotic (M) phase, the cell separates its DNA into two sets and divides its cytoplasm, forming two new cells.
what is the E2F
is a group of genes that encodes a family of transcription factors (TF) in higher eukaryotes.
what does the interphase consists of?
G1, s and G2
what is the g1 phase of the cell cycle
During the first gap phase, the cell grows physically larger, copies organelles, and makes the molecular building blocks it will need in later steps. The availability of growth factors controls the animal cell cycle at a point in late G1 called the restriction point; if growth factors are not available during G1, the cells enter a quiescent stage of the cycle called G0.
what is the S phase of the cell cycle
The cell synthesizes a complete copy of the DNA in its nucleus. It also duplicates a microtubule-organizing structure called the centrosome. The centrosomes help separate DNA during M phase.
what is the G2 phase of the cell cycle
During the second gap phase, the cell grows more, makes proteins and organelles, and begins to reorganize its contents in preparation for mitosis. G2 ends when mitosis begins
what occurs in the mitotic M phase of the cell cycle
During the mitotic (M) phase, the cell divides its copied DNA and cytoplasm to make two new cells. M phase involves two distinct division-related processes: mitosis and cytokinesis.
• In the prophase of mitosis, chromosomal material condenses to form compact mitotic chromosomes. The cytoskeleton is disassembled, and mitotic spindle is assembled.
• In the prometaphase, the chromosomal microtubules attach to kinetochores of chromosomes and are moved to the spindle equator.
• In the metaphase, chromosomes are aligned along the metaphase plate and are attached to both poles by microtubules.
• In the anaphase the centromeres split, and chromatids separate moving the chromosomes to opposite single poles.
• In the telophase, the chromosomes cluster at opposite poles. The nuclear membrane assembles around the clusters, with daughter cells formed by cytokinesis.
Non-mutagenic replication of every nucleotide once per cycle is essential; only one copy should be made, with no mutations.
what are the 4 DNA nucleotides monomers
• Purines:
o A - adenine
o G – guanine
• Pyrimidines:
o T - thymine
o C - cytosine
how are radio labelled nucleotides identified
Radiolabelled nucleotides (3H-thymidine) are incorporated into cells at DNA replication. Using X-ray photography or antibody staining, cells in S-phase may be identified. Flow-cytometric detection of cells stained with DNA dyes allows the discrimination of cells with variable DNA content. Cells in G1 phase (peak 1) contain half the DNA of cells after DNA replication in G2 and M (peak 2); cells in the process of replication (S-phase) contain an intermediate quantity.
what is the role of cyclin-dependant kinases (CDKs)
In order to drive the cell cycle forward, a cyclin must activate or inactivate many target proteins inside of the cell. Cyclins drive the events of the cell cycle by partnering with a family of enzymes called the cyclin-dependent kinases (Cdks). A lone Cdk is inactive, but the binding of a cyclin activates it, making it a functional enzyme and allowing it to modify target proteins.
how do cyclin-dependant kinases (CDKs) work
Cdk1 is the only on required to drive through the cell stages. Cyclin B1 and A2 are essential for normal cell cycle.
• At G1 phase: CDK 4 & CDK 6 binds to Cyclin D – Cyclin D levels are influenced by extracellular signals (mitogens, growth factors and survival factors). The main target of CDK 4 & 6 is Retinoblastoma protein (Rb). Dysfunction of the Rb protein (stuck in on position) may lead to uncontrolled proliferation, where mutations are likely.
• G1/S phase: CDK 2 binds to Cyclin E
• S phase: CDK 2 binds to Cyclin A
• M/ G2 phase: CDK 1 (aka Cdc25) binds to Cyclin B1
• CDKs are activated by activating phosphorylation of threonine around position 160.
• CDK-inhibitors are proteins that bind to CDK-cyclin complexes and block their activity.
o Wee1 kinase inhibits phosphorylation of threonine 14 & tyrosine 15 on CDK 1, inhibiting cell cycle progression
o CDK 1 phosphatase reverses the change of Wee1, leading to active CDK.
what is meant by cell cycle checkpoints
The availability of cyclins controls the activity of CDKs and promotes cell progression. CDKs become active via cyclin-binding; when complexed with M-phase cyclin, mitosis machinery is triggered, when complexed to S-phase cyclin, DNA replication is triggered.
There are also several checkpoints which ensure complete genomes are transmitted to daughter cells, and cells with damaged DNA do not replicate.
what are the different cell cycle checkpoints in the cell cycle
•At G1, cell size, growth factors & DNA damage are checked. If the cell doesn’t meet the requirements, it will leave the cell cycle and enter a resting state – G0.
oDNA damage causes p53 levels to increase, causing transcription of p21
op21 binds to PNCA – a component of DNA replication machinery – preventing its activity
oBy ensuring that cells don’t divide when their DNA is damaged, p53 prevents mutations; when p53 is defective or missing, mutations can accumulate quickly, potentially leading to cancer. Indeed, out of all the entire human genome
op53 is the single gene most often mutated in cancers
.
•At G2, un-replicated or damaged DNA are checked. If errors or damage are detected, the cell will pause to allow for repairs. Topoisomerase II is responsible for repairing DNA at this stage. If the checkpoint mechanisms detect problems with the DNA, the cell cycle is halted, and the cell attempts to either complete DNA replication or repair the damaged DNA. If the damage is irreparable, the cell may undergo apoptosis, or programmed cell death
oA signal is sent to a series of protein kinases, which phosphorylate and inactivate Cdc25
oThe dephosphorylation of M-Cdk is blocked, and it does not activate, preventing entry to mitotic phase
• At M (aka spindle checkpoint), chromosomal misalignment (i.e. the chromosome is not attached to the spindle) will stop the cycle. If a chromosome is misplaced, the cell will pause mitosis, allowing time for the spindle to capture the stray chromosome.
what is meant by PI3K signalling
PI3K signalling is a form of endocrine signalling. The pituitary releases growth hormone, which acts on tyrosine kinase receptors. A kinase is an enzyme that transfers phosphate groups to a protein or other target, and a receptor tyrosine kinase transfers phosphate groups specifically to the amino acid tyrosine, activating it. The signal relay pathway through PI3K, PTEN, AKT, mTOR and S6K1 or 4EBP results in gene expression & cell proliferation.
The PI3K/AKT/mTOR pathway is an intracellular signalling pathway important in regulating the cell cycle. In many cancers, this pathway is overactive, thus reducing apoptosis and allowing proliferation. In many kinds of breast cancer, aberrations in the PI3K/AKT/mTOR pathway are the most common genomic abnormalities (e.g. PIK3CA gene mutation).
what is meant by HER-2 signalling
HER-2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. The HER-2 receptor is a transmembrane tyrosine kinase receptor that consists of an extracellular ligand-binding domain, a transmembrane region, and an intracellular or cytoplasmic tyrosine kinase domain.
It is activated by the formation of homodimers or heterodimers with other epidermal growth factor (EGFR) proteins.
Further downstream molecular signalling cascades are activated, such as the Ras/Raf/mitogen-activated protein kinase (MAPK), the phosphoinositide 3-kinase/Akt, and the phospholipase Cγ (PLCγ)/protein kinase C (PKC) pathways that promote cell growth and survival and cell cycle progression.
describe the MAPK pathway:
When growth factor ligands bind to their receptors, the receptors pair up and act as kinases. The activated receptors trigger a series of events:
• Ras is activated
o KRAS ( K-ras or Ki-ras) is a gene that acts as an on/off switch in cell signalling. When it functions normally, it controls cell proliferation. When it is mutated, negative signalling is disrupted.
• Guanine nucleotide exchange factors (GEFs) are recruited
• GEF becomes capable of interacting with Ras proteins at the cell membrane to promote a conformational change and the exchange of GDP for GTP.
• Raf is recruited to the cell membrane, and activation stimulates a signalling cascade by phosphorylation of MAPK which successively phosphorylate and activate downstream proteins such as ERK1 and ERK2
• Transcription factors are activated promoting cell growth and division.
Over-expression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. The protein has become an important biomarker and target of therapy for approximately 30% of breast cancer patients. HER2-positive breast cancer has a faster growth rate than HER2-negative.
what is the pathology of breast cancer
488 (1%) genes are implicated in the development of cancer. Of these, 90% have somatic mutations; 20% have germline mutations (10% have both). Somatic mutations occur in a single cell and are not passed to offspring; germline mutations occur in gametes and may be inherited by the offspring of that cell, affecting many different types of cell.
Cancer cells behave differently than normal cells in the body, related to cell-division. Cancer cells may multiply without any growth factors, or growth-stimulating protein signals.
what are 2 types of mutations
Mutations stimulate cell survival and proliferation, and may be:
• Dominant (gain of function) – a single mutation event creates oncogenes - overactive positive cell cycle regulators.
• Recessive (loss of function) – two, or more, mutations eliminate tumour suppression activity - inactive negative regulators.
what is meant by oncogenes and how does it work
Oncogenes drive abnormal cell proliferation. They may represent the overactive form of normal cellular genes, called proto-oncogenes or alternatively, they may enter the cell as part of a virus. A proto¬-oncogene may become overactive and be converted into an oncogene due to mutation in coding sequence, gene amplification or chromosomal rearrangement.
what is meant by tumour superior genes
Tumour suppressors are genes that normally inhibit cell proliferation and tumour development. In tumour development, tumour suppressors are often lost or inactivated, usually requiring 2 mutational events; inactivation can occur through deletion, point mutation or epigenetic changes (where the gene does not mutate but is inactivated). This may occur due to nondisjunction, giving rise to unequal mitosis; random elimination of a chromosome results in recessive mutation of tumour suppressor.
what re the 3 types of tumour suppressor genes
There are 3 types of tumour suppressor:
• Caretakers – promote gene stability & control mutation rate
o Checkpoint genes (p53)
o DNA repair genes (BRCA)
• Gatekeepers – monitor cell division & death
o Cell cycle (Rb)
• Landscapers – control cellular microenvironment
how does the stress hormone stimulate further breast cancer
During and after diagnosis and treatment, almost 50% of cancer patients report anxiety and 25% report significant anxiety; 20% experience transient or long-term depression; and 15% are diagnosed with post-traumatic stress disorder.
Stress results in the production of the stress response hormones: cortisol, (Cort), norepinephrine (NE), and epinephrine (E) at physiological concentrations. Stress hormones can rapidly induce DNA damage and interfere with the DNA-damage repair process in pre-cancerous cells leading to cell transformation and tumorigenicity. They increase levels proteins involved in cell cycle regulation and progression and reduce levels of proteins that cause apoptosis (cell death).
how does cancer develop
A cell might first lose activity of a cell cycle inhibitor, an event that would make the cell’s descendants divide a little more rapidly. It’s unlikely that they would be cancerous, but they might form a benign tumour a mass of cells that divides too much. Over time, a mutation might take place in one of the descendant cells, causing increased activity of a positive cell cycle regulator. The mutation might not cause cancer by itself either, but the offspring of this cell would divide even faster, creating a larger pool of cells in which a third mutation could take place. Eventually, one cell might gain enough mutations to take on the characteristics of a cancer cell and give rise to a malignant tumour, a group of cells that divide excessively and can invade other tissues.
describe how tumours develop
- PIK3CA mutations most commonly occur concomitantly with loss of adenomatous polyposis coli (APC). APC has many functions, the most prominent is its capacity to regulate beta-catenin-mediated gene transcription in response to Wnt signalling. Unbound ß-catenin binds to Tcf/Lef gene, which transcribes for Cyclin B & D. Loss of APC leads to deregulated beta-catenin and hyperproliferative epithelium.
- Increased genetic instability, and loss of P53 (protein involved in G1 checkpoint preventing damaged DNA from replicating) leads to early adenoma. p53 is the gene most commonly mutated in human cancers, and cancer cells without p53 mutations likely inactivate p53 through other mechanisms
- The Rb protein is implicated in the G1 checkpoint; when Rb is permanently in on mode, G1 phase of cell cycle is continually driven – point of no return.
- HER-2 receptors are upregulated in tumour cells; hyperactivation of this signalling pathway & abnormal cell proliferation is observed
- K-Ras mutation/ activation disrupts negative signalling pathway causing unregulated proliferation into intermediate adenoma (MAPK pathway).
what are the properties acquired by cancer cells
• Sustaining proliferation signalling
o G1 phase is implicated, Rb protein function is lost.
• Activating invasion and metastasis
Cancer cells gain the ability to migrate to other parts of the body.
• Inducing Angiogenesis
o promoting growth of new blood vessels to give tumour cells a source of oxygen and nutrients
• Resisting cell death via lack of apoptosis
o Cancer cells also fail to undergo programmed cell death, or apoptosis, under conditions when normal cells would (e.g., due to DNA damage)
Emerging hallmarks
• Evading growth suppressors
o Secretion of immunosuppressive factors enables cancers to avoid destruction from the immune system.
• Enabling Replicative immortality
o Metabolic changes that support increased cell growth and division.
Enabling characteristics
• Promoting inflammation
• Genome instability allows mutations to accumulate more rapidly
what is the % of patients who get chemotherapy for breast cancer
34% of patients diagnosed with breast cancer have chemotherapy as part of their primary cancer treatment.
how can the risk of relapse be reduced?
The risk of recurrence can be reduced using adjuvant chemotherapy.
• Adjuvant = after primary surgery
• Neo-adjuvant = before surgery – reduces invasive surgery
o Locally advanced tumours
o Inflammatory tumours
o For larger tumours or those with large amounts of nodal involvement or inflammatory component, neoadjuvant chemotherapy may be used to shrink the tumour before surgery to improve the outcome and preserve remnant breast tissue
Although chemotherapy comprises part of a successful regimen for treating breast cancer, as many as 50% of patients fail to benefit due to the development of intrinsic and acquired multiple drug resistance
Risk factors associated with onset of a resistant phenotype: genetic predisposition such as mutations in a and b tubulins, and BRCA1/2; induction of expression of multi-drug resistance (MDR) proteins; alterations in spindle assembly checkpoints,cell cycle proteins and apoptosis
what is meant by mitotic inhibitors
Disrupt M phase of cell cycle, leading to cell arrest.
how does Taxanes distrupt the cell cycle
Taxanes (e.g. Paclitaxel)
Other taxanes include Docetaxel and Carbazitaxel. Paclitaxel is extracted from the bark of T. brevifolia (Pacific Yew); 12 slow-growing trees are required for the treatment of 1 patient.
Paclitaxel is a microtubule stabiliser. It acts during the telophase of M phase, binding to the β subunit of tubulin – the building block of microtubules. The resulting microtubule/paclitaxel complex does not have the ability to disassemble, blocking progression of mitosis and causing prolonged activation of the mitotic checkpoint. This triggers apoptosis or reversion to the G0-phase of the cell cycle without cell division.
Paclitaxel does not meet the requirements of good drug-likeness (RMM = 50326.5; 15 H-bond acceptors). It is Class IV (poorly permeable, poorly soluble) of the Biopharmaceutical Classification System, so is not ideal for oral delivery.
