PBL 7

9. 7 hallmarks of cancer: What are the molecular changes in the cells?

1.1 *Self-sufficiency in growth signals*. (accelerator stuck on) 1.2 *Insensitivity to anti-growth signals*. (brakes don't work) 1.3 *Evading programmed cell death*. (won't die when the body normally would kill the defective cell) 1.4 *Limitless replicative potential*. (infinite generations of descendants. No hayflick limit) 1.5 *Sustained angiogenesis*. (telling the body to give it a blood supply) 1.6 *Tissue invasion and metastasis*. (migrating and spreading to other organs and tissues)

24. How long do you have to be cancer free to be cured?

5 years

Term: Cancer geneticist

A person who specialises in genetics of cancer

Term: Prophylactic treatment

A prophylactic is a medication or a treatment designed and used to *prevent a disease from occurring*.

Term: ER and PR positive

About 80% of all breast cancers are "ER-positive." That means the cancer cells grow in response to the hormone estrogen. About 65% of these are also "PR-positive." They grow in response to another hormone, progesterone. If your breast cancer has a *significant number of receptors for either estrogen or progesterone*, it's considered hormone-receptor positive. Tumors that are ER/PR-positive are much more likely to respond to hormone therapy than tumors that are ER/PR-negative.

Term: Oophorectomy

An oophorectomy is a surgical procedure to remove one or both of a woman's ovaries.

Term: BRCA1 gene

BRCA1 and BRCA2 are *human genes that produce tumor suppressor proteins*. Specific inherited mutations in BRCA1 and BRCA2 most notably increase the risk of female breast and ovarian cancers, but they have also been associated with increased risks of several additional types of cancer. These proteins help repair damaged DNA and, therefore, play a role in ensuring the stability of each cell's genetic material. When either of these genes is mutated, or altered, such that its protein product is not made or does not function correctly, DNA damage may not be repaired properly. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

11. How does the anatomy of the breast change in breast cancer?

Breast lump was the most common symptom, recorded in about four-fifths of all women (83%). The next most commonly reported presenting symptoms were nipple abnormalities (7%), breast pain (6%), and breast skin abnormalities (2%).

8. How does this link to lump size and hardness (micro-calcifications)? How is it formed? What is it made of?

Calcium - forms when cells are being replaced too rapidly — not a direct sign of cancer, but is indicative of possibly malignancy.

19. How are secondary tumours formed?

Cancer cells may get carried in the bloodstream to other parts of the body. The cells may then *multiply to form secondary tumours (metastases)* in one or more parts of the body. These secondary tumours may then grow, invade and damage nearby tissues, and spread again.

5. What is the chain of referral in breast cancer? [BRIEF

GP, Oncologist, genetic counsellor, surgeon, MDT

Term: HER2

HER2 (*human epidermal growth factor receptor 2*) is a gene that can play a role in the development of breast cancer. If higher levels of it are found in a breast cancer, it is called HER2 positive breast cancer.

Term: Histological

Histological definition, the branch of biology dealing with the study of tissues.

Truncating mutation

In genetics, a point-nonsense mutation is a point mutation in a sequence of DNA that results in a *premature stop codon, or a point-nonsense codon in the transcribed mRNA*, and in a truncated, incomplete, and usually nonfunctional protein product.

Term: Invasive ductal carcinoma

Invasive ductal carcinoma (IDC), also known as infiltrating ductal carcinoma, is *cancer that began growing in a milk duct and has invaded the fibrous or fatty tissue of the breast outside of the duct*. IDC is the most *common* form of breast cancer, representing 80 percent of all breast cancer diagnoses.

7. Why does the breast cancer spread to the axilla?

Lymph nodes - metastasis

4. National screening programme for breast cancer in UK

NHS provides free breast screening every three years for *all women aged 47 and over*. Breast screening is a method of detecting breast cancer at a very early stage. This involves an x-ray of each breast - a mammogram. *Ultrasounds* - Usually used for women under 35 whose breasts are too dense or solid to give a clear picture with mammograms. Ultrasound can also show if a breast lump is solid, or if it contains fluid. A fluid filled lump is called a cyst. *Microcalcifications*: tiny calcium deposits usually found in an area of the breast where cells are being replaced more quickly than normal. *Needle Biopsy* - Insertion of a needle to extract tissue from target area.

20. What are the consequences of single and total mastectomy?

Simple or total mastectomy concentrates on the breast tissue itself: - The surgeon removes the entire breast. - The surgeon does not perform axillary lymph node dissection (removal of lymph nodes in the underarm area). Sometimes, however, lymph nodes are occasionally removed because they happen to be located within the breast tissue taken during surgery. - No muscles are removed from beneath the breast. Loss of self identity, post surgery depression general of confidence

Term: Stage II infiltrating ductal carcinoma

Stage 2 means the breast cancer is growing, but it is *still contained in the breast* or growth has *only extended to the nearby lymph nodes*. This stage is divided into groups: Stage 2A and Stage 2B. The difference is determined by the *size* of the tumor and whether the breast cancer has spread to the *lymph nodes*. Invasive ductal carcinoma (IDC), also known as infiltrating ductal carcinoma, is cancer that began growing in a milk duct and has invaded the fibrous or fatty tissue of the breast outside of the duct.

Term: Tamoxifen (what does it target?)

Tamoxifen is a nonsteroidal triphenylethylene derivative that *binds to the estrogen receptor*. It has both estrogenic and antiestrogenic actions, depending on the target tissue. Tamoxifen attaches to the hormone receptor in the cancer cell, blocking estrogen from attaching to the receptor. This *slows or stops the growth of the tumor by preventing the cancer cells from getting the hormones they need to grow*.

3. When do people get breast cancer? [age]

The vast majority of breast cancers are diagnosed in women *over the age of 50*.

18. Link of BRCA1 with ovarian and other cancers

While there may be other genes that predispose women to breast cancer and ovarian cancer, BRCA1 and BRCA2 are the most common and well-defined among them. BRCA-pathway functions are most required at the breasts and ovaries.

Term: menarche

the first occurrence of menstruation.

23. What is the follow up for cancer?

Radiotherapy, HER2 Suppressorsq

14. Relevance of oestrogen and progesterone in breast cancer and treatment

- Estrogen receptor present in the *nucleus* of certain target cells in the body. - Estrogen molecule enters passes through the target cell's membrane. - It then enters the nucleus. - Estrogen binds to its complementary receptor in the nucleus. - The shape of the receptor changes. - Estrogen-receptor complex then binds to specific DNA sites, called estrogen response elements - Estrogen-receptor complex binds to *coactivator proteins* and *more nearby genes become active*. - Breast cells: *estrogen causes cell proliferation of the cells lining the milk glands*, thereby preparing the breast to produce milk if the woman should become pregnant. When estrogen levels deplete at the end of the menstrual cycle, these cells deteriorate and die. - Progesterone receptor found in the cytoplasm of target cells. - When no binding hormone is present the carboxyl terminal inhibits transcription. When progesterone binds to the receptor, there is a structural change that removes the inhibitory action. After progesterone binds to the receptor, restructuring with dimerization follows and the complex enters the nucleus and binds to DNA. Transcription takes place, resulting in formation of messenger RNA that is translated by ribosomes to produce specific proteins. - Treatment: progesterone antagonists, antiprogestins. - Tamoxifen is a SERM. It blocks the action of estrogen (an antagonist) in breast tissue by binding to the estrogen receptors, thereby preventing estrogen molecules from binding to it. This means there is no change in shape of the receptor. Therefore, coactivators cannot bind to it, thus no transcription.

2. What are the risk factors for getting breast cancer? Smoking, alcohol, menarche, first child, genetics? [BRIEF]

- Gender: Being a *woman* is the main risk factor for developing breast cancer. - Age: The risk of developing breast cancer *increases as you get older*. - Ethnicity: more prevalent in *white women* compared to African-American women. - Genetic: some cancers result directly due to inherited mutations 2. *BRCA1 and BRCA2 mutations: The most common cause of hereditary breast cancer*. Women with these inherited mutations also have an increased risk for developing other cancers, particularly ovarian cancer. Family History: Breast cancer risk is higher among women whose close blood relatives have the condition Personal History: Breast cancer risk is higher if history of condition. Menstrual Periods: the *earlier the *menarche*, the higher the risk of developing breast cancer. This is because of longer exposure to oestrogen. Lifestyle: - Having *children* decreases risk. - Drinking *alcohol* increases risk. - *Obesity* after menopause increases risk (higher levels of leptin). - Long-term *smoking* increases risk

6. What is the breast self-examination procedure?

1) In the Shower Using the pads of your fingers, move around your entire breast in a circular pattern moving from the outside to the center, checking the entire breast and armpit area. Check both breasts each month feeling for any lump, thickening, or hardened knot. Notice any changes and get lumps evaluated by your healthcare provider. 2) In Front of a Mirror Visually inspect your breasts with your arms at your sides. Next, raise your arms high overhead. Look for any changes in the contour, any swelling, or dimpling of the skin, or changes in the nipples. Next, rest your palms on your hips and press firmly to flex your chest muscles. Left and right breasts will not exactly match—few women's breasts do, so look for any dimpling, puckering, or changes, particularly on one side. 3) Lying Down When lying down, the breast tissue spreads out evenly along the chest wall. Place a pillow under your right shoulder and your right arm behind your head. Using your left hand, move the pads of your fingers around your right breast gently in small circular motions covering the entire breast area and armpit. Use light, medium, and firm pressure. Squeeze the nipple; check for discharge and lumps.

17. How are BRCA1 and BRCA2 inherited?

1. Familial - inherits one wild type allele and one mutant, therefore only one carcinogenic even just occur. E.g environmental exposure such as x-rays or genetic exposure such as failed DNA replica-tion 2. Sporadic - this is not genetic, you inherit two healthy wild types - therefore, two events need to occur somatically for malignancy

12. Tests used in breast cancer

Breast screening is a method of detecting breast cancer at a very early stage. This involves an x-ray of each breast - a mammogram. Ultrasounds - Usually used for women under 35 whose breasts are too dense or solid to give a clear picture with mammograms. Ultrasound can also show if a breast lump is solid, or if it contains fluid. A fluid filled lump is called a cyst. Microcalcifications: tiny calcium deposits usually found in an area of the breast where cells are being replaced more quickly than normal. Needle Biopsy - Insertion of a needle to extract tissue from target area.

13. What are the different types and different stages of the types of breast cancer?

Ductal Carcinoma In Situ (DCIS) Invasive Ductal Carcinoma (IDC) IDC Type: Tubular Carcinoma of the Breast IDC Type: Medullary Carcinoma of the Breast IDC Type: Mucinous Carcinoma of the Breast IDC Type: Papillary Carcinoma of the Breast IDC Type: Cribriform Carcinoma of the Breast Invasive Lobular Carcinoma (ILC) Inflammatory Breast Cancer Lobular Carcinoma In Situ (LCIS) Male Breast Cancer Molecular Subtypes of Breast Cancer Paget's Disease of the Nipple Phyllodes Tumors of the Breast Metastatic Breast Cancer Tumours are graded between 1 and 3. Grading for non-invasive breast cancers such as ductal carcinoma in situ (DCIS) is different, and is defined as low, medium or high grade rather than 1, 2, or 3. Stage 0. The cancer has been diagnosed early. It started in the breast ducts or milk glands and has stayed there. You're likely to hear or see the words in situ, meaning "in the original place." Stage I. Starting at this level, breast cancer is called invasive, meaning it has broken free to attack healthy tissue. Stage 1A means the cancer has spread into the fatty breast tissue. The tumor itself is no larger than a shelled peanut, or there may be no tumor Stage IB means some cancer cells, but just tiny amounts, have been found in a few lymph nodes. Stage II. The cancer has grown, spread, or both. IIA means the tumor in the breast is still small, if there's one at all. There may be no cancer in the lymph nodes, or it may have spread to as many as three. A stage IIB breast tumor is bigger -- it may be the size of a walnut or as big as a lime. It may or may not be in any lymph nodes. Stage III. The cancer has not spread to bones or organs, but it's considered advanced, and it's harder to fight. IIIA means the cancer has been found in up to nine of the lymph nodes that form a chain from your underarm to your collarbone. Or it has spread to or enlarged the lymph nodes deep in your breast. In some cases there is a large tumor in the breast, but other times there's no tumor. IIIB means the tumor has grown into the chest wall or skin around your breast, even if it hasn't spread to the lymph nodes. IIIC means cancer has been found in 10 or more lymph nodes, or has spread above or below your collarbone. It's also IIIC if fewer lymph nodes outside the breast are affected but those inside it are enlarged or cancerous. Stage IV. Breast cancer cells have spread far away from the breast and lymph nodes right around it. The most common sites are the bones, lungs, liver, and brain. This stage is described as "metastatic," meaning it has spread beyond the region of the body where it was first found.

15. How do you test for HER2?

IHC test (ImmunoHistoChemistry): The ImmunoHistoChemistry test finds out if there is too much HER2 protein in the cancer cells. The results of the IHC test can be: 0 (negative), 1+ (also negative), 2+ (borderline), or 3+ (positive — HER2 protein overexpression). - Uses antibodies that target specific peptides or protein antigens. - These bound antibodies can then be detected using several different methods. - FISH test (Fluorescence In Situ Hybridization): The Fluorescence In Situ Hybridization test finds out if there are too many copies of the HER2 gene in the cancer cells. The results of the FISH test can be positive (HER2 gene amplification) or negative (no HER2 gene ampli-fication). - SPoT-Light HER2 CISH test (Subtraction Probe Technology Chromogenic In Situ Hybridi-zation): The SPoT-Light test finds out if there are too many copies of the HER2 gene in the cancer cells. The results of the SPoT-Light test can be positive (HER2 gene amplification) or negative (no HER2 gene amplification). - Inform HER2 Dual ISH test (Inform Dual In Situ Hybridization): The Inform HER2 Dual ISH test finds out if there are too many copies of the HER2 gene in the cancer cells. The results of the Inform HER2 Dual ISH test can be positive (HER2 gene amplification) or neg-ative (no HER2 gene amplification).

Term: Lymph node with thickened cortex

Lymph node cortical thickness and uniformity are the most important criteria for distinguishing between normal and abnormal nodes. Normal lymph nodes have a reniform shape, a uniformly hypoechoic cortex with a maximal thickness of 3 mm, smooth margins, and a central fatty hilum. Lymph nodes become *swollen* in response to illness, infection, or stress. Swollen lymph nodes are one sign that your *lymphatic system is working to rid your body of the responsible agents*.

Term: mammogram

Mammograms are used as a screening tool to detect early breast cancer in women experiencing no symptoms. They can also be used to detect and diagnose breast disease in women experiencing symptoms such as a lump, pain, skin dimpling or nipple discharge. Mammography is specialized medical imaging that uses a *low-dose x-ray* system to see *inside the breasts*.

Term: Axillary lymph node metastasis

Metastasis: the development of *secondary malignant growths* at a *distance from a primary site* of cancer. When cancer has spread to the axillary lymph nodes, the nodes may feel enlarged, or there may be a noticeable lump.

Term: Micro-calcifications

Microcalcifications are *tiny calcium deposits* that show up as small white specks on a mammogram. They are usually found in an area of the breast where *cells are being replaced more quickly than normal*. Microcalcifications are not usually due to cancer.

Term: Radiotherapy - when do you have it in breast cancer?

Radiation therapy usually begins *three to eight weeks after surgery* unless *chemotherapy* is planned. When chemotherapy is planned, radiation usually starts *three to four weeks after chemotherapy is finished*.

Term: TNM stage II tumour

The TNM system is the most widely used cancer staging system. - The *T* refers to the *size and extent* of the *main tumour*. The main tumour is usually called the *primary* tumour. - The *N* refers to the the *number of nearby lymph nodes that have cancer*. - The *M* refers to whether the cancer has *metastasised*. This means that the cancer has spread from the primary tumour to other parts of the body. When your cancer is described by the TNM system, there will be numbers after each letter that give more details about the cancer—for example, T1N0MX or T3N1M0. The following explains what the letters and numbers mean: Primary tumour (T) TX: Main tumour cannot be measured. T0: Main tumour cannot be found. T1, T2, T3, T4: Refers to the size and/or extent of the main tumour. The higher the number after the T, the larger the tumour or the more it has grown into nearby tissues. T's may be further divided to provide more detail, such as T3a and T3b. Regional lymph nodes (N) NX: Cancer in nearby lymph nodes cannot be measured. N0: There is no cancer in nearby lymph nodes. N1, N2, N3: Refers to the number and location of lymph nodes that contain cancer. The higher the number after the N, the more lymph nodes that contain cancer. Distant metastasis (M) MX: Metastasis cannot be measured. M0: Cancer has not spread to other parts of the body. M1: Cancer has spread to other parts of the body. Stage 0 Abnormal cells are present but have not spread to nearby tissue. Also called carcinoma in situ, or CIS. CIS is not cancer, but it may become cancer. Stage I, Stage II, and Stage III Cancer is present. The higher the number, the larger the cancer tumour and the more it has spread into nearby tissues. Stage IV The cancer has spread to distant parts of the body.

21. Impact of long term condition diagnosis on mental health

- Depression - Fear of being seen as a time waster / neurotic - Fear that family think symptoms are psychosomatic - Men view help-seeking as unmasculine - Embarrassment of sensitive area

1. What influences people to seek help?

- Public health campaigns - Family - Friends - GP - Family history

16. Normal function of BRCA1 and what goes wrong in breast cancer?

BRCA1 gene: Normally synthesises protein called breast cancer type 1 susceptibility protein. This is *responsible for DNA repair*. If mutated, this function is lost.