Breast Cancer

What is the G0 phase?

cell is in long-term rest. cells stay here if they don’t need to regularly multiply

What is the G1 phase?

cell grows in preparation for DNA replication

What is the S phase?

DNA synthesis phase

What is the G2 phase?

after the chromosomes have been duplicated the cell continues to grow and prepare the organelles to support 2 new cells

AKA safety gap to ensure everything has been properly duplicated

What is mitosis?

sister chromatids split to provide DNA for both daughter cells

What are the checkpoints that occur in the G1 or G2 phase?

detection of damaged DNA

What is the checkpoint that occurs in the M phase?

detection of improper spindles

What is the checkpoint that occurs in the S phase?

detection of incomplete replication

If any of these defects are detected in the cell cycle, the cell cannot continue through the cycle after the step with the defect. true or false?

true

What is p53?

a tumor suppressor gene that is the most common mutation seen in cancer

How does p53 work?

it works at the checkpoint between the G2/M transition

the levels of this protein increase when DNA damage is detected and it can inhibit progression to mitosis

What happens when there is a mutation with the p53 gene?

when both copies of the gene are dysfunctional, the cell cannot detect DNA damage before progressing through the cell cycle

What is the Rb protein and how does it work?

acts at the G1/S checkpoint and can inhibit progression to DNA synthesis if damage is detected

What are the apoptotic proteins that p53 can activate or enhance the activity of?

Puma, Noxa, Bax, Bak, BIM

the activation of these then leads to cytochrome C release from mitochondria which activates a variety of caspases which eventually execute apoptosis

How do cancer cells suppress the apoptotic response?

upregulating the anti-apoptotic proteins or downregulating the pro-apoptotic proteins

What are some places where things can go wrong and ultimately lead to cancer?

chromosome

telomere

abnormal chromatin remodeling

DNA mutations

What is translocation?

a type of chromosomal abnormality in which a chromosome breaks and a portion of it reattaches to a different chromosome

What is inversion?

a chromosomal mutation in which a chromosome segment is removed, rotated through 180 degrees, and reinserted in the same location

What is internal deletion?

part of a chromosome or sequence of DNA is left out during DNA replication

What are cancer stem cells?

small percentage of cancer cells that have unlimited self-renewal potential

they are thought to be one of the reasons cancer recurs

What is the role of lobules in the breast?

producing milk

What is the role of ducts in the breast?

carry milk from lobules to nipple

What is stage 0 breast cancer?

breast cancer that hasn’t spread through the walls of the ducts or to other nearby tissues

What is ductal carcinoma in situ?

cancer cells are found along the sides of the milk duct within the breast and have not spread through the walls of the ducts and to other nearby tissues

stage 0 breast cancer

What is invasive ductal carcinoma?

the cancer has spread outside the breast duct to surrounding normal tissue

What is lobular carcinoma in situ?

cancer cells in lobule and hasn’t spread to nearby tissue

What are some pearls of lobular carcinoma?

condition rarely becomes invasive cancer

having LCIS in one breast increases the risk of developing breast cancer in either breast

What are the risk factors for breast cancer?

increasing age

personal or family history

radiation therapy to chest

post menopausal obesity

first period before age 12

beginning menopause after age 55

having your first child after age 35

having no children

postmenopausal combined estrogen/progesterone hormone therapy

alcohol

breast density

What is the role of BRCA 1?

helps to initiate HR by triggering end resection

What happens if there is a mutation in the BRCA 1 or 2 gene?

homologous recombination can’t happen and DNA might not get repaired well

What is the most common subtype of breast cancer?

HR positive and HER2 negative

Describe anthracyclines

DNA intercalators that distort the DNA helix which interferes with transcription, replication, and repair

forms a complex with DNA and topoisomerase II which helps remove DNA supercoiling. When anthracyclines form this complex, it leads to a jumbled mess and ultimately apoptosis

What is the MOA of taxanes?

inhibitors of mitosis by promoting microtubule formation by stabilizing the tubule and GDP complex which makes the microtubules more rigid and the mitotic spindle can’t form properly

prevent microtubules from being broken down

What is an example of a taxane?

paclitaxel (Taxol)

What are examples of platinum agents?

cisplatin

carboplatin

oxaliplatin

What is the MOA of platinum agents?

bind to nucleophilic sites on DNA which leads to intrastrand and interstrand cross-linking distorting the DNA double helix and thus preventing replication

What drug classes are used to treat ER+ breast cancer?

SERMs (selective estrogen receptor modulators)

SERDs (selective estrogen receptor degraders)

Why are SERMS selective?

they have distinct effects depending on what tissue they are acting on

How is tamoxifen selective?

it has anti-proliferative effects on breast tissue, but has agonistic effects on the uterus, bone, and heart

What are some examples of SERMs?

raloxifene

tamoxifen

What is the MOA of tamoxifen?

binds estrogen receptor in a similar fashion to estradiol but the additional side chain causes the receptor to be in an antagonist conformation blocking the cofactor’s ability to bind and you don’t get expression of those genes

What is the downside to tamoxifen?

it acts as an agonist on endometrial tissue leading to cell proliferation and increased risk of endometrial cancer

What is the MOA of raloxifene?

acts as an estrogen receptor antagonist in the breast, estrogen receptor agonist in the bone, and estrogen receptor antagonist in the uterus

Why is raloxifene preferred over tamoxifen?

it acts as an antagonist in the uterine tissue unlike tamoxifen which acts as an agonist and can cause endometrial cancer

What is an example of a SERD?

fulvestrant

What is the MOA of fulvestrant?

binds to estrogen receptors and causes those receptors to not be able to dimerize and thus can’t translocate to the nucleus and there is no transcription of estrogen sensitive genes

What is the MOA of aromatase inhibitors?

inhibit aromatase which is responsible for converting androstenedione to estrone which is the primary form of estrogen in postmenopausal women. Less estrogen means less signaling to estrogen receptors to replicate

What are the type I aromatase inhibitors?

formestane and exemestane

What are the type II aromatase inhibitors?

anastrozole, letrozole

What is the difference between type I and type II aromatase inhibitors?

type I are steroidal analogues of androstenedione and type II are nonsteroidal

What are examples of aromatase inhibitors?

anastrozole

letrozole

exemestane

Which drug is used for HER2 positive targeted therapies?

trastuzumab

What is trastuzumab?

a humanized IgG1 monoclonal antibody that binds to the extracellular domain IV of HER2

What is the MOA of trastuzumab?

binds to extracellular domain IV of HER2 and prevents HER2 from sending growth signals. Blocks dimerization of HER2 receptor with other receptors. Binding to HER2 can also induce antibody-dependent immune cell-mediated cytotoxicity

Which drug is used for hormone positive targeted therapies as CDK4/6 inhibitors?

palbociclib

What type of breast cancer is palbociclib used to treat?

ER positive and HER2 negative

What is palbociclib used in combination with?

letrozole as initial endocrine based therapy in postmenopausal women

fulvestrant in women with disease progression after endocrine based therapy

What is the MOA of palbociclib?

inhibits CDK4 and CDK6 which are signaling molecules that tell the cell to grow and divide

What are examples of CDK4/6 inhibitors?

palbociclib

ribociclib

abemaciclib

What is a description of stage 0 breast cancer?

disease contained to ducts/lobules of breast. noninvasive

What is the goal of treatment for stage 0 breast cancer?

curative

What is a description for stage 1 breast cancer?

disease exists in normal breast tissue. invasive cancer

What is the goal of treatment for stage 1 breast cancer?

curative

What is a description of stage II breast cancer?

disease exists in nearby (up to 3) lymph nodes. invasive cancer.

What is the goal of treatment for stage II breast cancer?

curative

What is a description of stage III breast cancer?

disease exists in 4 or more lymph nodes or manifests in chest wall, breast skin, or other nearby manifestations. invasive cancer.

What is the goal of treatment for stage III breast cancer?

curative

What is a description of stage IV breast cancer?

disease exists in non breast organs, distant lymph nodes. metastatic disease.

What is the goal of treatment for stage IV breast cancer?

prolong life, improve quality of life

What are the 3 different types of breast cancer?

ER/PR+

HER2+

triple negative

What are the unmodifiable risk factors for breast cancer?

gender

age greater than 50

environment

genetics

personal history

family history

lifetime estrogen exposure

first period before age 12

What are the modifiable risk factors for breast cancer?

hormone replacement therapy

alcohol use

late first pregnancy

post menopausal obesity/increased BMI

oral contraceptive use

radiation exposure

What are the 2 common surgeries for breast cancer?

breast conserving

total tissue removal

Describe breast conserving surgeries.

lumpectomy or quadrantectomy

these surgeries look to excise just the tumor, leaving the majority of the breast tissue

Describe total tissue removal.

mastectomy

the entirety of the breast tissue is removed and is often recommended for preventative reasons

What are the 2 types of radiation?

external beam and internal

Describe external beam radiation.

a beam of photons that is dosed every day over several weeks

Describe internal radiation.

radiation is introduced into the body either surgically or through consumption

What are the side effects of radiation?

fatigue

hair loss

skill reactions

shortness of breath

What are the pearls of anthracyclines?

they are vesicants meaning they can cause blistering and destruction of tissue at infusion site

discolors a patient’s urine turning it red

UNIQUE side effects of heart toxicity and hepatotoxicity

What are the pearls of alkylating agents such as cyclophosphamide?

must be co-administered with hydration and mesna to prevent hemorrhagic cystitis

UNIQUE side effects of hemorrhagic cystitis, myelosuppression

What are the pearls of taxanes?

must be co-administered with diphenhydramine, steroids, and H2RAs due to high risk of anaphylaxis

must be given before platinum agents if administered

UNIQUE side effects of peripheral neuropathy, myalgia, arthralgia, hepatotoxicity

What are the pearls of platinum agents?

causes the most severe nausea and vomiting of any class

UNIQUE side effects of peripheral neuropathy, neuropathy, ototoxicity, nephrotoxicity

Why are hormone therapeutics best used in post-menopausal women?

these drugs actively compete against hormone production in the ovaries and there is less estrogen produced in the ovaries after menopause

Why are SERDs usually reserved for later stage cancers?

because it blocks all activity of estrogen in the body not just in the breast

What are the drug classes used to treat nausea and vomiting associated with cancer therapy?

5-HT3 receptor blockers

NK-1 receptor blockers

corticosteroids

dopamine antagonists

What are the 5-HT3 receptor blockers?

ondansetron, palonosetron

What are the NK-1 receptor blockers?

fosnetupitant, aprepitant

What is a corticosteroid used to treat nausea and vomiting?

dexamethasone

What is a dopamine antagonist used for nausea and vomiting?

prochlorperazine

What medications are used to treat diarrhea?

imodium (loperamide)- OTC

lomotil (diphenoxylate/atropine)- prescription

What are some medications used to treat constipation?

senna, polyethylene glycol, methylnaltrexone, lubiprostone

Which constipation medications are OTC?

senna and polyethylene glycol

Which constipation medications are used to treat opioid-induced constipation?

methylnaltrexone and lubiprostone

What are some prevention things patients can do for mucositis?

oral hygiene

caphosol

cryotherapy

mucosal protectants

What are some things to treat mucositis?

topical pain relievers

magic mouthwash

corticosteroids

ice-chips

What can be used to treat alopecia?

cold cap

What is considered a normal neutrophil count?

greater than 1500 cells/uL

What are the preventative treatment medications for neutropenia?

neupogen (filgrastim)

neulasta (pegfilgrastim)

work by stimulating production of neutrophils

What are some symptoms of hot flashes?

rapid or irregular heart beat

sleep disturbances

flushing or reddened face and neck

perspiration

cold chills