Prostate Cancer Flashcards
Epidemiology
- median age at diagnosis is 67
- overall incidence is 163.0/100,000 men/yr
- overall mortality is 26.7/100,000 men/yr
- 30k men/yr develop castrate resistant prostate cancer
- 1 in 6 men will be diagnosed with prostate cancer in their lifetime
- b/w 1984-1991, 30-40% presented with advanced disease; today only 5-15% have metastatic disease at presentation
prostate cancer risk factors
known: *age *ethnicity *family history suspected *diet unlikely *fertility medical myths *vasectomy *benign prostate hyperplasia (BPH) *bike riding
age is the dominant risk factor. what are the percentages of risk for the different age groups?
- age 50-59: 9%
- age 60-69 12.5%
- age 70-79 32%
- age 80-89 37%
ethnicity
- the highest age adjusted incidence of prostate cancer occurs in African-Americans
- nearly 2x the incidence that occurs in non-African americans
family history
- 2-3x increased risk in patients with primary relative prostate cancer <70
- familial clustering identified
- BRCA2
diet, obesity and physical activity
- 1/3 of cancer deaths in the US are attributed to nutritional factors
- soon will exceed tobacco as the most significant lifestyle cause of cancer mortality
- obesity, physical inactivity and excess caloric intake increase risk of several types of cancer
- obesity related to cancers of breast (postmenopausal), kidney, endometrium, esophagus, prostate and colon (especially in men) and gallbladder (especially in women)
what are the ways of diagnosis prostate cancer?
- PSA
- digital rectal exam
- biopsy
- imagine studies
PSA
- prostate specific antigen is a protein produced by the epithelial cells lining the prostate ducts. Its function is to liquefy the seminal fluid
- it is prostate tissue-specific not prostate cancer-specific
- 4-10: 25% chance of having prostate cancer
- > 10: 67% chance of having prostate cancer
what are some PSA confounders?
- benign prostatic hypertrophy
- prostatitis
- age
- ejaculation
- digital rectal exam
- medicines
- e.g. 5-alpha reductase inhibitors
- herbal preparations
- beware of compounds with estrogenic properties that lower androgen levels
what are some ways to improve the diagnostic accuracy of PSA?
- age-specific PS
- lowering the threshold for abnormal in younger men
- percent-free PSA
- PSA occurs in 2 major forms- free and bound
- the % of free PSA is lower in men with prostate cancer. percent-free of <25% is worrisome for cancer
- PSA velocity
- the change of PSA over time. a rate of rise faster than 0.75/yr is worrisome for cancer
digital rectal exam
- good specificity
- poor sensitivity
- low cost
- poor compliance
- inter-observer variability
What is the staging of prostate cancer?
- PSA
- digital rectal exam
- trans rectal ultrasound
- gleason score
- bone scan
- +/- CT scan or MRI
- biopsy and TNM staging system
- Tumor, Nodes, Metastases
what is prostate cancer T1 disease?
- cannot be felt
- T1a- cancer found in =< 5% TURP specimen
- T1b- cancer found in >= 5% TURP specimen
- T1c- cancer found as a result of PSA elevation only
what is prostate cancer T2?
- can be felt during DRE
- T2a- felt on one side of prostate
- T2b- felt on both sides of prostate
what is prostate cancer T3?
- has spread beyond the prostate
- T3a- extra capsular extension
- T3b- tumor invades seminal vesicles(s)
what is prostate cancer T4?
- has invaded local organs
- bladder invasion
- invasion into surrounding pelvic side wall
- may cause pain in joints and back
what are some sites of metastasis?
bone lymph nodes lung lier CNS
pathology
- adenocarcinoma (gland-like) accounts for 95% of prostate cancers
- variant cancers account for the remaining 5%:
- neuroendocrine cancer
- sarcomatoid cancers
- lymphoma
- transitional cell (urothelial) cancer
prostate cancer grade
- the gleason system is based on the glandular pattern of the adenocarcinoma as identified at relatively low magnification
- both the primary and secondary architectural patterns are assigned a grade from 1 (most differentiated) to 5 (least differentiated).
gleason grade distribution
6 low grade
7 intermediate grade
8-10 high grade
primary therapy early stage disease
- prostatectomy
- open
- robot-assisted laparascopic
- external beam radiation
- brachytherapy
- cryosurgery
- active surveillance
primary therapy
- surgery is reserved form men less than 70-75 years old, with a life expectancy of 15 years, and likely organ confined disease:
1. PSA at diagnosis
2. clinical stage
3. gleason score
external beam radiation
- better option than prostatectomy if:
- higher risk to have extra-prostatic disease
- older patients (>70-75)
- patients with concurrent medical illnesses that diminish candidacy for surgery
- often given concurrently with short term hormonal therapy which enhances radiation activity
active surveillance
- appropriate option for low risk patients:
- PSA<10mg/dl
- T1c or T2a disease
- gleason 6
- no more than 3 biopsy cores positive
- no more than 50% of anyone core positive
- patients undergo semi-annual-clinical evaluations and annual repeat biopsies to exclude disease progression or upstaging with sampling
what are the prostate cancer molecular features?
- the role of the androgen receptor in cell signaling and proliferation of prostate cancer cells
- understanding mechanisms for castrate resistant disease (CRPC)
- treatment options for CRPC
AR-Testosterone Pathway General Principles
- the testis are stimulated by the hypothalamus-pituitary axis and produces 90% of a man’s androgens. remaining 10%:
- adrenal glands
- prostate cancer cells
- AR is a cytoplasmic receptor. it needs to undergo binding to androgens and multiple configurations to enter the nucleus
- once within the nucleus AR binds to DNA with the help of co-activators and elicits biologic response. in prostate cancer these include:
- cell proliferation
- lack of apoptosis
- PSA production
AR biologic pathway
- key
- SHBG= sex hormone binding globulin
- DHT= dihydrotestosterone
- HSP= heat shock protein
- AR= androgen receptor
- ARA70= androgen receptor agonist 70
- GTA= general transcription apparatus
Treatment Options Androgen Deprivation Therapy
- bilateral orchiectomies
- lutenizing hormone releasing hormone (LHRH) antagonist therapy
- degeralex
- LHRH agonist therapy
- leuprolide…
- often combined with an androgen receptor antagonist (flutamide, bicalutamide…)
Biology of Castrate Resistant Prostate Ca
*activation of AR at low levels of T/DHT
-changes in the PCA cell that allows for phosphorylation of the AR
-enhances the binding of the AR to T/DHT
*AR mutations
-mutations in the ligand binding domain affect the ligand binding pocket and liberalize the spectrum of AR agonists to a wider range of steroid hormones and pharmaceutical antiandrogens
*indirect mechanisms of AR activation
-deregulation of apoptotic genes
-neuroendocrine differentiation of prostatic cells
-decreased expression of coexpressors
+change in CoA:CoR alters AR activity in the setting of low levels DHT
*increased levels of AR protein without mutations
*incomplete blockade of AR-ligand production
-medical or surgical castration does not result in undetectable androgen levels
+adrenals androgens
+intracrine mechanism
what are the treatment options for CRPC advanced disease?
- alternative endocrine manipulations
- chemotherapy
- immunotherapy
- skeletal protective therapy
