Overview of Carcinoma Prostate and Genetics

A brief overview about Prostate Cancer regarding various aspects

1. Overview of Prostate Cancer By Dr. Ayush Garg

2. Anatomy Of Prostate The prostate is a walnut-sized gland located in front of the rectum and below the bladder. It surrounds the urethra, the tube-like channel that carries urine and semen through the penis. The primary function of the prostate is to produce seminal fluid, the liquid in semen that protects, supports, and helps transport sperm .

3. Base of the Prostate The base is directed upward near the inferior surface of the bladder. The greater part of this surface is directly continuous with the bladder wall. Apex of the Prostate The apex is directed downward and is in contact with the superior fascia of the urogenital diaphragm. Anatomy Of Prostate

4. Anatomy Of Prostate Blood supply Inferior vesical artery Derived from the internal iliac artery Supplies blood to the base of the bladder and prostate Capsular branches of the inferior vesical artery Help identify the pelvic plexus Nerve supply Neurovascular bundle Lies on either side of the prostate on the rectum Derived from the pelvic plexus , arising from the S2-4 and T10-12 nerve roots Important for erectile function.

5. Prostatic Zonal Anatomy There are four zones of the prostate : the peripheral zone (PZ) , transition zone (TZ) , Central zone, and anterior fibromuscular stroma zone .

6. Peripheral zone (PZ) 70% of cancers Transitional zone (TZ) 20% TZ prostate cancers are relatively nonaggressive PZ cancers are more aggressive Tend to invade the peri -prostatic tissues.

7. Lymphatic Drainage

8. Regional Lymph Nodes Pelvic Hypogastric Obturator Iliac (internal, external) Sacral (lateral, presacral , promontory [ Gerota's ])

9. Metastatic Lymph Nodes Distant lymph nodes lie outside the confines of the true pelvis. The distant lymph nodes include the following: Aortic ( paraaortic lumbar) Common iliac Inguinal, deep Superficial inguinal (femoral) Supraclavicular Cervical Scalene Retroperitoneal

10. Epidemiology Second leading cause of cancer death in men from western countries It is one of the 10 leading cancer sites in males in India, accounting for about 4 % all male cancers Age-adjusted annual incidence 176 per 100,000 in USA, whereas only 7.1 in Mumbai and 4.3 in Bangalore (NCRP 1990-96)

11. Etiology Family history: 2-3 fold increased risk in men with a first degree relative. Hereditary association : Early onset of disease and a Mendelian autosomal dominant inheritance– accounting for <10% of all cases but 40% in younger men in <55 years. Racial Factors : Striking differences in incidence and mortality between the Black and White population, more common in blacks. Environmental Factors: also responsible for ethnic differences, as Asians migrating to USA have higher incidence of prostate cancer.

12. Etiology Diet : one of the most important modifiable risk factors -- high fat intake increases risk whereas diets rich in carotenoids (tomato based products containing lycopene) and vitamin-E are protective. No association with cigarette smoking, alcohol use, height and weight and blood group. No data regarding viral origin. No convincing evidence that Vasectomy increases risk of prostate cancer

13. Pathology Adenocarcinoma 95% of prostate cancers Developing in the acini of prostatic ducts Rare histopathologic types of prostate carcinoma Occur in approximately 5% of patients Include Small cell carcinoma Mucinous carcinoma Endometrioid cancer (prostatic ductal carcinoma) Transitional cell cancer Squamous cell carcinoma Basal cell carcinoma Adenoid cystic carcinoma ( basaloid ) Signet-ring cell carcinoma Neuroendocrine cancer

14. CLINICAL MANIFESTATIONS EARLY STAGE Asymptomatic Cancer is in the peripheral zone LOCALLY ADVANCED DISEASE Obstructive / irritative voiding Hesitancy Intermittent urinary stream Decreased force of stream --- May have growth into the urethra or bladder neck Retention of urine Hematuria Hematospermia Renal failure Pelvic pain ADVANCED DISEASE (spread to the regional pelvic lymph nodes) Edema of the lower extremities Pelvic and perineal discomfort METASTATIC DISEASE Bone pain Spinal cord compression symptoms Paraperesis

15. Hematuria - prostatic urethra/ trigone involvement Hematospermia Extra prostatic spread- often asymptomatic/ extensive dis. Rectal involvement- Hematochezia Constipation Intermittent diarrhoea Abdomino -pelvic pain Renal impairment due to prolonged bladder outlet obstruction. Fluid retention/ electrolyte imbalance

16. Involvement of neurovascular bundles/ GUD: ------- Impotence/ pelvic pain/ priapism Advanced disease- metastatic symptoms Bony- pain / pathological fracture/ Spinal tenderness Spinal cord compression- neurological deficits/ sensory-motor changes/ bladder-bowel dysfunction Pelvic / Para aortic LAP- edema of abdominal wall, genitalia or lower extremities/ mass abdomen Adrenal/ lung/ skin metastasis. PNS- SIADH/ Cushing syndrome.

17. STAGING OF PROSTATE CANCER

18. T1a: Tumor with an incidental histologic finding in 5% or less of tissue resected T1b: Tumor with an incidental histologic finding in more than 5% of tissue resected

19. T2a: Tumor that involves one-half of one side or less T2b: Tumor that involves more than one-half of one side but not both sides T2c: Tumor that involves both sides

20. T3a: Extraprostatic extension (unilateral or bilateral) T3b: Tumor invades seminal vesicle(s)

21. T4: Tumor is fixed or invades adjacent structures other than seminal vesicles such as ● external sphincter ● rectum ● bladder ● levator muscles and/or ● pelvic wall

22. DIAGNOSTIC WORK-UP Laboratory Complete blood cell count, blood biochemistry Serum PSA (total, free, percentage free) Plasma acid phosphatases (prostatic/total) Radiographic imaging Transrectal ultrasonography (for biopsy guidance) Biopsy/Needle biopsy of prostate ( transrectal , transperineal ) Chest radiograph (high risk for metastatic disease) Computed tomography of pelvis. Radioisotope bone scan Magnetic resonance imaging. PET CT Scan for metastasis in high risk cases

23. Diagnosis • Signs and symptoms of Prostatism • Abnormal DRE : although correlates poorly with the volume and extent of cancer, an integral part of the algorithm. • Serum PSA : usually > 4 ng /ml With increasing PSA level, chance of getting cancer increases, but less likely to be organ confined. • TRUS guided Biopsy : 1) to establish the diagnosis. 2) to report extent and grade of cancer in each core. 3) to document presence of PNI or ECE.

24. LABORATORY INVESTIGATIONS PROSTATE SPECIFIC ANTIGEN Serine protease glycoprotein secreted by prostatic epithelium Carcinoma specific Normal : 0.4 - 4 ng/ml (upper limit 2.6 ng/ml) t 1/2 : 2.2― 3.2 ±0.1 days Mild elevation 4 ― 10 ng/ml Significant elevation >10 ng/ml Sensitivity ― 85% Specificity – 65-70% Estimated rate of cancer detection by PSA screening ― 1.8-3.3% Carcinoma with normal PSA ― 25%

25. Age specific PSA : Age PSA 40-50 0-2.5 60-70 0-4.5 70-80 0-6.5 Pretreatment serum PSA is also predictive of EPE and SVI : PSA Rate of organ-confined disease 4 -10 ng /ml 53% - 70% 10 -20 ng /ml 31% - 56% Roach’s Probability of ECE, SVI and LNI : ECE+ = 3/2×PSA +(GS-3)×10 SVI+ = PSA +(GS-6)×10 LNI+ = 2/3×PSA +(GS-6)×10

26. PSA density (PSAD) The PSAD was introduced particularly for men with normal DRE and PSA levels of 4–10 ng/mL in order to differentiate between BPH and prostate cancer. The PSAD is calculated by dividing the serum PSA level by the prostate volume, as measured by TRUS. The threshold level of 0.15 or above indicates prostate cancer, while 0.15 or below indicates benign disease.

27. PSA Velocity (PSAV) The concept of the PSAV was developed to aid the early diagnosis of nonpalpable organ-confined cancer, since such cases show high PSA changes in a short period of time (i.e., increased PSAV). The PSAV is calculated using a formula that incorporates at least three PSA levels measured at 6 month (or more) intervals.

28. PSA Bounce Phenomenon The PSA bounce is a temporary rise in PSA level after radiation therapy. It may occur anywhere between about 1 and 3 years after treatment The magnitude of the bounce lies in the range 0.5–2 ng/mL and may last from a few months to around a year The reason for the bounce is not known Testosterone recovery after hormonal treatment may cause a PSA bounce in patients receiving androgen ablation therapy along with radiotherapy

29. PSA Relapse PSA relapse definition after RT ASTRO consensus → three consecutive increases in PSA is the definition of biochemical failure after radiation therapy. The date of failure should be the midpoint between the post-RT nadir PSA and the first of the three consecutive rises. Phoenix definition → (1) a rise by 2 ng/mL or more above the nadir PSA should be considered the standard definition for biochemical failure after external RT with or without hormonal treatment; (2) the date of failure should be determined “at call” (not backdated).

30. Digital Rectal Examination Cornerstone of the physical examination/ instrumental in staging Sim’s lateral position. Organ palpation: Craniocaudal and transverse dimension Consistency / Mobility Any firm/ elevated area and its size. Typical finding ca prostate - Hard, nodular, asymmetrical, may or may not be raised above the surface of gland and is surrounded by compressible prostatic tissue. Prostatic induration - BHP nodule/ calculi/ infection/ granulomatous prostatitis / infarction Specificity- 50% and Sensitivity- 70% Only 25-50% of men with an abnormal DRE have cancer. DRE + PSA specificity 87%

31. Prostate Anatomy on DRE

32. TRANRECTAL ULTRASONOGRAPHY(TRUS) Extraprostatic extension Sensitivity-66% Specificity- 46% Accuracy- 58% Seminal vesicle invasion Echogenic abnormalities Ant. displacement and enlargement of SV

33. Gleason’s Score Donald F. Gleason in 1966 created a unique grading system for prostatic carcinoma based solely on the architectural pattern of the tumor .

34. Gleason’s Score Prostate cancer has a pronounced morphological heterogeneity and usually more than one histological pattern is present. The primary and secondary pattern, i.e. the most prevalent and the second most prevalent pattern are added to obtain a Gleason score or sum. Gleason Score= Predominant pattern (1-5) + Secondary pattern (1-5) Best Score=2, Worst Score=10

35. IMAGING CXR Pulmonary metastasis Miliary pattern Axial skeletal survey : Specific sites of bony pain Osteoblastic secondaries USG abdomen-pelvis: hydroureteronephrosis large post void residual urine volume retroperitoneal lymphadenopathy Liver mets .

36. CT SCAN Primary role Size determination of the gland Assess pelvic LN metastasis Treatment planning in RT Extra Prostatic Extension: Loss of periprostatic fat planes Bladder base deformity Obliteration of the normal angle b/w the SV and post. aspect of UB LN involvement Abnormality in size Sensitivity 25% Reserved for patients with higher PSA values (>20-25 ng/ml) CT guided FNAC

37. MRI Superior to CT in defining prostate apex, NVB and anterior rectal wall Better delineation of periprostatic fat involvement T1w- provides high contrast b/w water density structures i.e. Prostate, SV and fat, NVB, perivesical tissue and LNs T2w fast spine echo- zonal anatomy, architecture of SV Ca Prostate: A focal, peripheral region of decreased signal intensity surrounded by a normal(high intensity) peripheral zone BHP: centrally located nodules of similar signal Primary staging sensitivity- 69% Endorectal surface coil MRI- accuracy of 54-72% staging the primary and detects SVI and ECE

38. Indications: High likelihood of capsular invasion and LN metastasis Abnormal DRE PSA>20 Poorly differentiated ca Sensitivity to locate gland tumor- 79% and specificity- 55% LN detection- Low sensitivity but high specificity

39. 99 Tc BONE SCAN Clinically apparent metastatic disease limited to bone in 80-85% of patients of metastatic ca prostate Osteoblastic secondaries MC sites of metastasis Vertebral column- 74% Ribs- 70% Pelvis- 60% Femora- 44% Shoulder girdle-41% Indications: Pretherapy Early stage disease-T 1 -T 2 with PSA > 20 ng / ml GS≥ 8 Bony pain T 3 -T 4 –Symptomatic patients High grade tumor Base line: Elderly, patients with h/o arthritis, to document degenerative changes that may later be interpreted as metastatic osseous disease and to assess t/t effectiveness

40. What is a Prostate-Specific Membrane Antigen (PSMA) study? PSMA studies are performed on newly diagnosed prostate cancer patients to determine if the disease has spread to pelvic lymph nodes. The study is also performed on patients who have had their prostate gland removed and have an increase in prostate-specific antigen (PSA) blood levels. PSMA is a membrane glycoprotein which is overexpressed manifold on prostate cancers, and the expression increases with Tumor Aggressiveness, Androgen-independence, Metastatic Disease, Disease recurrence

41. Ga-68 PSMA PET/CT Imaging identifies tumor cells expressing PSMA antigen with excellent sensitivity & specificity, thereby detecting lesions remaining unidentified by conventional methods. The study involves a special molecule called a monoclonal antibody developed in a laboratory and designed to bind to the prostate-specific membrane antigen on cancer cells. This antibody is paired with a radioactive material called Gadolinium 68 that can be detected by a gamma camera. When injected into the patient’s bloodstream, the radioactive antibody travels and attaches to cancer cells. The gamma camera then produces three-dimensional images of the tumor and its location inside the body.

42. This 73-year-old man was recently diagnosed with prostate cancer and has an elevated PSA. PET/CT shows the intense activity in the prostate cancer (arrow) and the spread to the left pelvic bone (b).

43. T reatment Depends on stage, patient's age and GC EARLY LOCALLY ADVANCED METASTATIC 3 risk group Stage Initial PSA GS LOW RISK T 1 –T 2a <10 ng/ml ≤ 6 INTERMEDIATE RISK Bulky T 2b 10- 20 7 HIGH RISK ≥ T 2c >20 8-10 ( D'Amico et al ) Localized disease Observation Radical radiotherapy Radical prostatectomy Cryoablation Locally advanced disease Radical radiotherapy Hormonal therapy Metastatic disease Palliative RT Hormonal therapy Chemotherapy RISK STRATIFICATION STAGE PSA GLEASONS SCORE

44. INITIAL RISK STRATIFICATION AND STAGING WORKUP FOR CLINICALLY LOCALIZED DISEASE Risk Group Clinical/Pathologi c Features Very low Has all of the following: cT1c Grade Group 1 PSA <10 ng/mL Fewer than 3 prostate biopsy fragments/cores positive, ≤50% cancer in each fragment/core PSA densit y <0.15 ng/mL/g Low Has all of the following but does not qualify for very low risk: cT1–cT2a Grade Group 1 PSA <10 ng/mL Has all of the Has all of the following: 1 IRF Grade Group 1 or 2 <50% biopsy cores positive (eg, <6 of 12 cores) Intermediate following: No high-risk group features N o very-high-risk group features Has one or more intermediat e risk Favorable intermediate Has one or more of the following: 2 or 3 IRFs Grade Group 3 ≥ 50% biopsy cores positive (eg, ≥ 6 of 12 cores) factors (IRFs):  cT2b–cT2c  Grade Group 2 or 3  PSA 10–2 ng/mL Unfavorable intermediate High Has no very-high-risk features and has exactly one high-risk feature: cT3a OR Grade Group 4 or Grade Group 5 OR PSA >20 ng/mL Very high Has at least one of the following: cT3b–cT4 Primary Gleason pattern 5 2 or 3 high-risk features >4 cores with Grade Group 4 or 5

45. Life Expectancy Options < 10 years Observation 10 to 20 years Active Surveillance > 20 years Active Surveillance RT Surgery Very L ow Risk

46. Life Expectancy Options < 10 years Observation > 10 years Active Surveillance RT Surgery Low Risk

47. Life Expectancy Initial Therapy Adjuvant Therapy < 10 years Observation RT ADT (short course) > 10 years RT ADT (short course) Surgery RT if adverse features ADT if LN positive Intermediate Risk

48. Initial Therapy Adjuvant Therapy RT ADT (long course) Surgery RT if adverse features ADT (long course) if LN positive High Risk

49. Initial Therapy Adjuvant Therapy RT ADT (long course) Surgery RT if adverse features ADT (long course) if LN positive Treat like metastatic disease, with ADT alone (selected patients) Very High Risk

50. ACTIVE SURVEILLANCE (AS) AND WATCHFUL WAITING (WW) AS generally consists of DRE and PSA every 3–6 months with routine repeat biopsy in 1–2 yrs with definitive treatment given if disease progresses. The goal of AS is to avoid or defer therapy (and side effects) until necessary. WW watches for symptoms that may arise from prostate cancer rather than regimented PSA, DRE, and biopsy, typically in men not suitable for aggressive treatment. WW may forgo possibility of curative treatment but symptoms are addressed

51. SURGERY

52. Radiotherapy

53. RADIOTHERAPY Adjuvant Radical Palliative Techniques: Conventional 3D CRT IMRT & IGRT SBRT Proton Therapy Brachytherapy

54. Salvage Radiotherapy Post RP recurrent disease Radical Radiotherapy T1, T2, T3, T4a Uresectable , Elderly , frail, comorbid condition Refusal for surgery Prohibitive morbidity due to surgery Post op Radiotherapy pT3/4 Close & positive margins Extracapsular extension Invasion to Seminal vesicles Extraprostatic extension multiple nodes R1 resection Pre op PSA >10ng/ml Pre op PSA velocity >2 ng/ ml/year

55. Target Volumes CTV = entire prostate +/- seminal vesicles +/- LN. ■ Low-risk prostate cancer CTV = entire prostate only. ■ Intermediate-risk prostate cancer CTV = prostate + proximal 1 cm of the bilateral seminal vesicles. ■ High-risk prostate cancer CTV = prostate + proximal 2 cm of the bilateral seminal vesicles (consider entire seminal vesicles if grossly involved) +/- LN regions. ■ Definition of the PTV ■ PTV: With CBCT IGRT, an 8 to 10 mm expansion is used, except posteriorly, where a 5 to 8 mm margin is used. The PTV expands into the rectum, whereas the CTV does not. GTV adenocarcinoma of the prostate is not visualized well and therefore is not contoured separately. TARGET LOW RISK INTERMEDIATE RISK HIG RISK CTV1 PROSTAE +/- PROXIMAL SEMINAL V E SICL E S (74 G Y) PROSTATE +PROX. SEMINAL VESICLE(76-78GY) PROSTATE=GROSS ETRACAPSULAR DISEASE &PROX.SEMINL VESICAL(76- 78GY) CTV2 -- DISTAL SEMINAL VESICALS(56 GY) DISTAL SEMINAL VESICLES AND LN(56 GY)

56. Dose/Fractionation Regimen Preferred Dose/Fractionation Moderate Hypofractionation (Preferred) 3 Gy x 20 fx 2.7 Gy x 26 fx 2.5 Gy x 28 fx 2.75 Gy x 20 fx Conventional Fractionation 1.8–2 Gy x 37–45 fx 2.2 Gy x 35 fx + micro-boost to MRI-dominant lesion to up to 95 Gy (fractions up to 2.7 Gy) SBRT Ultra-Hypofractionation 9.5 Gy x 4 fx 7.25–8 Gy x 5 fx 6.1 Gy x 7 fx 6 Gy x 6 fx

57. Brachytherapy It is also a dose escalation method when combined with EBRT. Low Risk Disease: Brachy only High Risk Disease: EBRT + Brachy

58. LDR Brachy As Brachy only: I 125 144 Gy , Pd 103 125 Gy . After EBRT 40-50 Gy: I 125 110 Gy, Pd 103 90 Gy. HDR Brachy As Brachy only: 9.5Gy twice daily for 2 days or 10.5Gy in 3# over one day. After EBRT: 9.5Gy in 2# over one session.

59. IODINE 125 PALLADIUM 103 T 1/2 (days) 59.4 16.97 Energy(keV) 27.4 21 Form Seeds Seeds Implant type Permanent Permanent Dose rate 7 19 Mean 0.42 1.3 activity/seed Monotherapy 145Gy mPD 125Gy mPD dose +EBRT dose 110Gy mPD 100Gy mPD TVL(mm) Pb 0.01 0.03

60. CHEMOTHERAPY Abiraterone Docetaxel Enzalutamide Cabazitaxel /carboplatin Olaparib for HRR (category 1) Radium-223 for symptomatic bone metastases (category 1) Rucaparib for BRCA mutation

61. HORMONAL THERAPY MECHANISMS OF ANDROGEN AXIS BLOCKADE

62. The androgen- signaling axis and its inhibitors. Testicular androgen synthesis is regulated by the gonadotropin-releasing hormone (GnRH)–LH axis, whereas adrenal androgen synthesis is regulated by the corticotrophin-releasing hormone (CRH)-ACTH axis. GnRH agonists and corticosteroids inhibit stimulation of the testes and adrenals, respectively. Abiraterone inhibits CYP17, a critical enzyme in androgen synthesis. Bicalutamide , flutamide , and nilutamide competitively inhibit the binding of androgens to androgen receptors; enzalutamide also blocks the translocation of the ligand bound AR complex to the nucleus and from binding to DNA. DHEA, dehydroepiandrosterone ; DHEA-S, dehydroepiandrosterone sulphate; DHT, dihydrotestosterone; AR, androgen receptor; ARE, androgen-response element.

63. Ablation of androgen source Inhibition of LHRH or LH Inhibition of androgen synthesis Antiandrogens Orchiectomy DES Leuprolide Aminogluthemide Cyprotene acetate Goserelin Ketoconazole Flutamide Triptorelin Biclutamide Histrelin Nilutamide Cetrorelix Abarelix

64. RT + SHORT-TERM ADT Randomized trials of stADT vs. no ADT report that adding 3–6-mo ADT improves bPFS by 10–25% and CSS by 3–8%.

65. RT + LONG-TERM ADT For high-risk men, long-term ADT improves DFS, CSS, and OS vs. no ADT or 4–6-mo ADT. Current standard for most high-risk men is 2–3 yrs ADT, but 18 months may be reasonable for those with limited high-risk features or comorbidity.

66. Bone-seeking radiopharmaceuticals P hosphorus-32 S trontium-89 S amarium-153-EDTMP Radium-223 is an alpha-emitting radiopharmaceutical Lu-177–PSMA-617 Myelosuppression is the predominate toxicity associated with all of the bone seeking radioisotopes .

67. Schedule Frequency First follow up 4-6 weeks after RT 0-1 years Every 3-4 months 2-5 years Every 6 months 5+ years Annually Examination History & Physical Examination Complete History & Physical Examination Annual DRE Laboratory Tests PSA every 6-12 months for 5 years and then annually Imaging Studies Based on clinical indication only Follow Up

68. GERMLINE TESTING Pre-test Considerations The panel recommends inquiring about family and personal history of cancer, and known germline variants at time of initial diagnosis. Testing I f criteria are met, germline multigene testing that includes at least BRCA1, BRCA2, ATM, PALB2, CHEK2, HOXB13, MLH1, MSH2, MSH6, and PMS2 is recommended Post-test Considerations Post-test genetic counseling is strongly recommended if a germline mutation (pathogenic/likely pathogenic variant) is identified. Cascade testing for relatives is critical to inform the risk for familial cancers in all relatives.

69. It is recommended in patients with a personal history of prostate cancer in the following scenarios By prostate cancer stage or risk group (diagnosed at any age) Metastatic, regional (node positive), very-high-risk localized, or high-risk localized prostate cancer GERMLINE TESTING

70. It may be considered in patients with a personal history of prostate cancer in the following scenarios By prostate cancer tumor characteristics (diagnosed at any age) Intermediate-risk prostate cancer with intraductal/cribriform histology By prostate cancer AND a prior personal history of any of the following cancers: exocrine pancreatic, colorectal, gastric, melanoma, upper tract urothelial, glioblastoma, biliary tract, and small intestinal GERMLINE TESTING

71. Germline testing is recommended in patients with a personal history of prostate cancer in the following scenarios ≥1 first-, second-, or third-degree relative with: Breast, colorectal or endometrial cancer at age≤50y Ovarian, male breast or exocrine pancreatic cancer at any age metastatic, regional, very-high-risk, or high-risk prostate cancer at any age ≥1 first-degree relative (parent or sibling) with prostate cancer at age ≤60 y ≥2 first-, second-, or third-degree relatives with breast and prostate cancer at any age ≥3 first- or second-degree relatives with: Lynch syndrome-related cancers, especially if diagnosed <50 y: colorectal, endometrial, gastric, ovarian, exocrine pancreas, upper tract urothelial, glioblastoma, biliary tract, and small intestinal cancer A known family history of familial cancer risk mutation especially in: BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2, and EPCAM

72. SOMATIC TESTING Pre-test Considerations The panel recommends inquiring about family and personal history of cancer, and known germline variants at time of initial diagnosis. Testing Tumor testing for alterations in homologous recombination DNA repair genes, such as BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2, and CDK12, is recommended TMB testing and Tumor testing for MSI-H or dMMR is recommended in patients with metastatic or regional castration-resistant prostate cancer Post-test Considerations Post-test genetic counseling to assess for the possibility of Lynch syndrome is recommended if MSI-H or dMMR is found

73. THANK YOU!