Alan H. Bryce, MD

Lynch syndrome (LS) is one of the most common hereditary cancer disorders and includes multiple urologic cancers within its spectrum. This autosomal dominant syndrome was one of the first hereditary cancer disorders to be identified and affects approximately 1 in 279 people.

 LS is historically known as hereditary nonpolyposis colorectal cancer (HNPCC) but is also associated with urothelial, prostate, testicular, and adrenal malignancies (

The carcinogenic mechanism of LS is caused by a mutation within the mismatch repair (MMR) genes, with the most common mutations being in the mutL homolog 1 (

), and postmeiotic segregation increased 2 (

 Mutations in the epithelial cellular adhesion molecule (EpCAM) can also lead to silencing of 

 MMR genes work together to identify and excise DNA mismatches during DNA synthesis, and mutation of a single protein in this pathway can lead to dysfunction of the entire repair system. The inherited germline mutation alone is not enough to lead to disruption of the MMR system. The second normal allele must be inactivated as well, typically through epigenetic silencing, somatic mutation, or loss of heterozygosity.

 The most common urologic cancer associated with LS is upper tract urothelial cancer (UTUC). It is rare, with an incidence of 2 in 100,000 people per year.4 However, MMR deficiency is seen in 5% to 11% of all patients with UTUC. The MMR genes most commonly associated with UTUC are 

 Urologists evaluating patients with UTUC who display certain characteristics should suspect an underlying genetic syndrome. Young patients, bilateral tumors, abnormal pathologic analysis, or family history compatible with LS all warrant further evaluation for LS.   

The risk of developing UTUC in a patient with LS is about 22 times higher than that of the general population and is estimated at between 0.4% and 20%.

A review of 288 patients with LS in Denmark showed that 22% developed UTUC and 17% developed urothelial carcinoma of the bladder. The mean age at diagnosis was 61, and 

 mutations were seen in 73% of cases. In addition, men and women appear equally affected in those with LS.

 Tumor stage and development of subsequent bladder cancer do not appear to differ in patients with LS versus sporadic patients.3 Bilateral tumors are more common in LS, and previous studies have observed bilateral tumors in 46% of patients.

Due to increased risk of UTUC among patients with LS, screening for urothelial cancer is recommended though there is no consensus on screening approach. Many groups use annual urinalysis with subsequent microscopic hematuria evaluation, because this is relatively low cost and minimally invasive.

 Other groups suggest addition of urogram phase to surveillance scans in those patients who had previous colorectal cancer (CRC).

 Annual computed tomography urogram or renal ultrasound may be particularly beneficial in patients with known 

mutation, because this is the MMR gene most commonly associated with UTUC. The National Comprehensive Cancer Network (NCCN) specifically recommends starting yearly urinalysis in patients with

Genetic testing for MMR mutations should be performed in certain patients with UTUC. Metcalfe et al screened patients without prior history of LS and with UTUC for risk of LS using the Amsterdam II criteria (

) and immunohistochemical (IHC) testing. This identified 13.9% of patients who were considered at risk for LS. Subsequent genetic testing confirmed that 5.2% of patients had LS.

 Therefore, those with positive screen using Amsterdam II criteria as well as those with positive IHC testing for MMR mutation should undergo genetic testing.

Bladder cancer occurring in multiple members of a family is still more likely to be a result of shared environmental risk factors than of heredity. However, emerging data demonstrate increased risk of bladder cancer in patients with LS, especially in men and those with 

mutations. In the previously cited article from Denmark, 17% of patients with LS may develop urothelial cancer of the bladder.

 A second study, from Canada, showed a lower percentage (6.21%) of patients with LS and 

mutations with bladder cancer; however, this was still significantly higher than the general Canadian population.

 These observations are likely high enough to justify a yearly urinalysis staring at age 30 in patients with known LS and 

Inclusion of prostate cancer as an LS-associated cancer remains controversial despite being clearly defined by Ryan et al in 2014.11This meta-analysis and systematic review showed that there is a 3.67-fold relative risk for developing prostate cancer in patients with MMR mutations, especially 

(95% CI, 2.32-6.67). Other studies have shown comparable results confirming increased prostate cancer risk in patients with LS.

Men with prostate cancer meeting certain criteria should be tested for LS. Based on the 2017 Philadelphia Prostate Cancer Consensus Conference, the recommendation is to screen for MMR gene mutations in men with family history of LS or with 2 or more blood relatives with an LS-associated cancer.

 These recommendations are similar to those for UTUC, though they do not specifically recommend use of the Amsterdam II criteria.

There are no data to suggest earlier onset of prostate cancer or higher stage at diagnosis. Some have proposed PSA screening starting at age 40; however, studies have shown a median age at diagnosis ranging from age 59 to 69 years.

 Therefore, men with LS should be strongly encouraged to undergo yearly PSA and physical exam testing. However, screening starting earlier than age 55 years is not supported by the literature.

The relationship between LS and testicular cancer is not well established. Current literature is conflicting, with some data showing up to 33% of testicular germ cell tumors containing MSI compared to other studies showing no MSI and no MMR deficiency on histopathologic analysis.

Due to the rarity of adrenocortical carcinoma (ACC), association with LS is difficult to establish. ACC is associated with poor prognosis and affects only about 1 to 2 patients per million each year.12 Various case studies have reported incidence of ACC within patients with LS and 

 mutations and, in a combined prospective and retrospective study, MMR mutations were found in 1.5% to 3.2% of patients with ACC.

 These data are not adequate to encourage screening for ACC in patients with LS; however, they do suggest that ACC should be a consideration when evaluating patients with LS with adrenal masses.

Lynch syndrome is one of the most common hereditary malignancy syndromes and is associated with multiple urologic cancers. To apply this knowledge of LS to daily practice, we should keep in mind the following:

UTUC is the third most common LS-associated cancer.

 mutations should undergo yearly urinalysis and microhematuria workup as indicated; they may also benefit from yearly renal ultrasound or CT urogram.

Patients with UTUC or prostate cancer meeting the Amsterdam II criteria or having abnormal immunohistochemical testing on pathology should undergo genetic screening for LS.

In patients with LS presenting with adrenal mass, ACC should be considered.

Beyond treating patients for urologic cancers, it is our role as urologists to identify patients at risk for undiagnosed Lynch syndrome and provide appropriate screening in this population.

 is associate professor of medicine at Mayo Clinic, Phoenix, Arizona.

1. Win AK, Jenkins MA, Dowty JG, et al. Prevalence and penetrance of major genes and polygenes for colorectal cancer. 

. 2017;26(3):404-412. doi:10.1158/1055-9965.EPI-16-0693

2. Huang D, Matin SF, Lawrentschuk N, Roupret M. Systematic review: an update on the spectrum of urological malignancies in Lynch syndrome. 

. 2018;4(3):261-268. doi:10.3233/BLC-180180

3. Mork M, Hubosky SG, Rouprêt M, et al. Lynch syndrome: a primer for urologists and panel recommendations. 

. 2015;194(1):21-29. doi:10.1016/j.juro.2015.02.081

4. Rouprêt M, Zigeuner R, Palou J, et al. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. 

. 2011;59(4):584-594. doi:10.1016/j.eururo.2010.12.042

5. Van der Post RS, Kiemeney LA, Ligtenberg MJ, et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. 

. 2010;47(7):464-470. doi:10.1136/jmg.2010.076992

6. Hubosky SG, Boman BM, Charles S, et al. Ureteroscopic management of upper tract urothelial carcinoma (UTUC) in patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer syndrome). 

. 2013;112(6):813-819. doi:10.1111/bju.12008

7. Gupta S, Provenzale D, Llor X, et al. NCCN guidelines insights: genetic/familial high-risk assessment: colorectal, version 2.2019. 

. 2019;17(9):1032-1041. doi:10.6004/jnccn.2019.0044

8. Metcalfe MJ, Petros FG, Rao P, et al. Universal point of care testing for Lynch syndrome in patients with upper tract urothelial carcinoma. 

. 2018;199(1):60-65. doi:10.1016/j.juro.2017.08.002

9. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. 

. 1999;116(6):1453-1456. doi:10.1016/s0016-5085(99)70510-x

10. Skeldon SC, Semotiuk K, Aronson M, et al. Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer. 

. 2013;63(2):379-385. doi:10.1016/j.eururo.2012.07.047

11. Ryan S, Jenkins MA, Win AK. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. 

. 2014;23(3):437-449. doi:10.1158/1055-9965.EPI-13-1165

12. Lim A, Rao P, Matin SF. Lynch syndrome and urologic malignancies: a contemporary review. 

. 2019;29(4):357-363. doi:10.1097/MOU.0000000000000639

13. Raymond VM, Everett JN, Furtado LV, et al. Adrenocortical carcinoma is a Lynch syndrome-associated cancer. 

. 2013;31(24):3012-3018. doi:10.1200/JCO.2012.48.0988

Articles

Research indicates Lynch syndrome is associated with urothelial, prostate, and other urologic cancers.

Urologic implications of Lynch syndrome

The use of immune checkpoint inhibitors (CPIs) has transformed cancer care in the last decade, but prostate cancer has not yet joined the immunotherapy revolution despite many clinical trials. Most recently, the IMbassador 250 study of atezolizumab (Tecentriq) added to enzalutamide (Xtandi) (NCT03016312) showed no benefit to adding atezolizumab.

Although it is clear that most patients with prostate cancer do not benefit from the currently available CPIs, it is nevertheless apparent that certain molecular subtypes of metastatic castrate-resistant prostate cancer (mCRPC) that can benefit from immunotherapy can be identified by genomic testing. We have many good new treatments for prostate cancer, but metastatic disease remains incurable and will be the cause of death for most patients. They will die from prostate cancer, not just with it. As long as that remains true, interest in immunotherapy for prostate cancer will remain high.

Although the ideal answer to this interest is to enroll patients in clinical trials, there are still scenarios in which nontrial treatment is the best available option. What follows is our approach to CPIs in patients with advanced prostate cancer.

Biologic differences in gene expression profiling and the presence of germline and somatic mutations exist in men with prostate cancer. National Comprehensive Cancer Network guidelines now recommend germline testing for all men with high-risk, very high-risk, or metastatic prostate cancer. We also conduct somatic (tumor) testing of all patients with metastatic disease and retesting whenever progression develops on a line of systemic therapy.

The adoption of genomic profiling with next-generation sequencing (NGS) has proven that there is significant diversity of mutational patterns in the tumors of men with metastatic prostate cancer.

 Genetic testing can identify patients who would benefit from PARP inhibitors such as olaparib (Lynparza) and rucaparib (Rubraca), and it can also identify patients whose tumors are more likely to respond to CPIs. These subtypes have a common characteristic of having mutations associated with DNA repair defects

 and include deficient mismatch repair genes (dMMR)/microsatellite instability-high (MSI-H), overexpression of PD-1 T-cell receptor and its ligand (PD-L1), high tumor mutational burden (TMB), and tumors with 

Although CPIs are less toxic for the average patient than chemotherapy, they are not benign and carry a small but real risk of treatment-related mortality and a 10% to 20% risk of hospitalization across many studies. They are also expensive therapies that have to be given intravenously (IV). However, we believe in being thoughtful about when and to whom we recommend CPIs 

 and limit them to patients whose genomics suggest a meaningful chance of response.

Subtypes of prostate cancer responsive to CPIs

Tumors that lack the dMMR mechanism are hypermutated compared with tumors without such MMR defects, and the neoantigens from these additionalmutations are more immunogenic. The use of NGS is encouraged to look for dMMR/MSI-H in all patients with advanced prostate cancer. Pembrolizumab (Keytruda) received a blanket FDA approval for patients with dMMR/MSI-H prostate cancer that progressed on prior treatments.

 An initial study in mCRPC showed clinical response in a patient with dMMR/MSI-H, treated with combination pembrolizumab and enzalutamide, suggesting that a high neoantigen load could predict responses to CPIs.

In a subsequent case series focusing on mCRPC, a minority of 3.1% (32 patients) had dMMR/MSI-H PC. Among the 11 patients who received PD-1/PD-L1 therapy, 55% had a decline in prostate-specific antigen (PSA), and 45% achieved a durable clinical benefit for as long as 19 months.

The open-label basket phase 1b KEYNOTE-028 trial studied pembrolizumab 10 mg/kg IV every 2 weeks for 24 months. It included 245 patients with mCRPC; 35 (14%) were positive for PD-L1. Among the 23 of 35 patients who were positive for PD-L1 who received pembrolizumab, the overall response rate (ORR) was 17%, with stable disease in 35%, progressive disease in 39%, median duration of response of 13.5 months, and median overall survival of 8 months. These findings were confirmed by KEYNOTE-199, a phase 2 trial using pembrolizumab 200 mg IV every 3 weeks for 21 cycles in 539 patients with docetaxel-refractory mCRPC.8 This study showed a PD-L1 overexpression of 32% in mCRPC and 8% in primary prostate cancer.

 In the PD-L1-positive cohort including 133 patients, there was an ORR of 7%, a median duration of response (mDOR) of 16.8 months, a complete response (CR) in 2 patients, and a median overall survival of 9.5 months.

Of note, studies exploring PD-1/PD-L1 expression in prostate cancer use different techniques and thresholds, which result in highly variable frequencies of positivity. In summary, these combined results suggest that up to 32% of advanced prostate cancers may use the PD-L1 pathway to escape immune system detection. Patients with mCRPC and the PD-L1 subtype have a small but meaningful and sometimes durable benefit from single-agent pembrolizumab.

 Patients with mCRPC seem to have a higher TMB compared with patients earlier in the disease course.

 In general, the tumors with higher TMB correlate with dMMR. A preliminary report from the CHECKMATE 650 trial (NCT029855957) using combination ipilimumab (Yervoy) and nivolumab (Opdivo) had better outcomes in patients with high TMB compared with low TMB (TMB cutoff not reported). Results showed an ORR of 58% in both chemotherapy-naive (60% vs 0%) and after taxane based-chemotherapy (50% vs 0%).

 is a tumor suppressor protein involved in genomic stability.

 Preclinical studies have suggested that biallelic 

 mutations are associated with higher neoantigens, tumor-infiltrating lymphocytes, and higher sensitivity to CPIs.

 An initial retrospective study demonstrated CPI sensitivity in 8 patients receiving PD-1 inhibitors as fourth- to sixth-line treatment. These heavily pretreated patients had a 38% PSA decline of more than 50% and a median PFS of 6.6 months.

 These results were corroborated in a retrospective study with 46 patients with 

 mutations (34 biallelic mutations). In a cohort of 5 patients treated with a PD-1 inhibitor, 40% achieved a PSA response.

Finally, a larger retrospective multicenter study included 60 patients with prostate cancer who had somatic loss-of-function 

 mutations. Nine patients were treated with a PD-1 inhibitor (5 with pembrolizumab, 4 with nivolumab) as 4th- to 6th-line treatment, with 33% having a PSA response and median PFS of 5.4 months.

 An ongoing prospective clinical trial (NCT03570619) is examining the predictive role of CDK12 as a biomarker for the use of CPI in prostate cancer.

 Selected POLE and POLD mutations can generate tumors associated with very high TMB without MSI-H. These mutations have been found in about 2% of prostate cancers.17 A case report has been described in an exceptional responder to pembrolizumab with a documented POLE V411L mutation.

 Similarly, a patient with a POLD1 D402N, MSH2 mutation, and high TMB has been reported with a good clinical response to pembrolizumab.

In our practice, we actively sort patients onto different treatment paths based on the genetic signature of their tumors. A small but meaningful percentage of patients will have genetic aberrations that predict responsiveness to CPIs, and the results for those lucky patients can be dramatic. We try to enroll patients on immunotherapy trials as much as possible. These trials often involve combinations of existing drugs but may also involve entirely new drugs that will be more effective for mCRPC.

We recently reported results from a phase 1 study of PT-112 in patients with a median of 6.5 lines of prior therapy. In this trial, 10 patients treated with PT-112 had a median overall survival of 15.1 months. We have also combined PT-112 with avelumab (Bavencio), with accrual to that study ongoing.

There are many possibilities yet to explore, and we need to find a way to expand immunotherapy to all patients with mCRPC. In the meantime, NGS can identify the patients who are most likely to respond to CPIs while also identifying patients who carry an inherited cancer susceptibility gene and patients who will benefit from PARP inhibitors.

is a hematology/oncology fellow at Mayo Clinic, Phoenix, Arizona, and 

is an associate professor of medicine at Mayo Clinic, Phoenix, Arizona.

1. Chung JH, Dewal N, Sokol E, Mathew P, Whitehead R, Millis SZ, et al. Prospective comprehensive genomic profiling of primary and metastatic prostate tumors. 

2. Hansen AR, Massard C, Ott PA, et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. A

3. Campbell BB, Light N, Fabrizio D, Zatzman M, Fuligni F, de Borja R, et al. Comprehensive analysis of hypermutation in human cancer. 

4. Fay AP, Antonarakis ES. Blocking the PD-1/PD-L1 axis in advanced prostate cancer: are we moving in the right direction? 

5. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency.

6. Graff JN, Alumkal JJ, Drake CG, Thomas GV, Redmond WL, Farhad M, et al. Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. 

7. Abida W, Cheng ML, Armenia J, Middha S, Autio KA, Vargas HA, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. 

8. Antonarakis ES, Piulats JM, Gross-Goupil M, Goh J, Ojamaa K, Hoimes CJ, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study. 

9. Ryan MJ, Bose R. Genomic alteration burden in advanced prostate cancer and therapeutic implications. 

10. Sharma P, Pachynski RK, Narayan V, Flechon A, Gravis G, Galsky MD, et al. Initial results from a phase II study of nivolumab (NIVO) plus ipilimumab (IPI) for the treatment of metastatic castration-resistant prostate cancer (mCRPC; CheckMate 650). 

11. Antonarakis ES. Cyclin-dependent kinase 12, immunity, and prostate Cancer. 

12. Wu YM, Cieślik M, Lonigro RJ, Vats P, Reimers MA, Cao X, et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. 

13. Barrero M, Rediti M, Crespo M, Dolling D, Rescigno P, Messina C, et al. Tumor-infiltrating lymphocytes in biallelic-CDK12 mutated prostate cancer. 

14. Antonarakis ES, Isaacsson Velho P, Agarwal N. CDK12-altered prostate cancer: clinical features and therapeutic outcomes to standard systemic therapies, PARP inhibitors, and PD1 inhibitors. Paper presented at: European Society of Medical Oncology Annual Meeting; September 29, 2019; Barcelona, Spain. Accessed May 27, 2020. https://oncologypro.esmo.org/meeting-resources/esmo-2019-congress/CDK12-altered-prostate-cancer-Clinical-features-and-therapeutic-outcomes-to-standard-systemic-therapies-PARP-inhibitors-and-PD1-inhibitors

15. Reimers MA, Yip SM, Zhang L, Cieslik M, Dhawan M, Montgomery B, et al. Clinical Outcomes in Cyclin-dependent Kinase 12 Mutant Advanced Prostate Cancer. 

16. Antonarakis ES, Velho PI, Fu W, Wang H, Agarwal N, Santos VS, et al. CDK12-altered prostate cancer: clinical features and therapeutic outcomes to standard systemic therapies, poly (ADP-ribose) polymerase inhibitors, and PD-1 inhibitors. 

17. Wang F, Zhao Q, Wang YN, Jin Y, He MM, Liu ZX, et al. Evaluation of POLE and POLD1 mutations as biomarkers for immunotherapy outcomes across multiple cancer types. 

18. Lee L, Ali S, Genega E, Reed D, Sokol E, Mathew P. Aggressive-variant microsatellite-stable POLE mutant prostate cancer with high mutation burden and durable response to immune checkpoint inhibitor therapy. 

19. Guedes LB, Antonarakis ES, Schweizer MT, Mirkheshti N, Almutairi F, Park JC, et al. MSH2 loss in primary prostate cancer. 

20. Bryce AH, Costello BA, Infante JR, Ames TD, Jimeno J, Karp DD. PT-112 in advanced metastatic castrate-resistant prostate cancer (mCRPC), as monotherapy or in combination with PD-L1 inhibitor avelumab: findings from two phase I studies. Poster presented at: 2020 Genitourinary Cancers Symposium; February 13, 2020; Chicago, IL. 

 2020;(supplement 6), abstract 83. Accessed May 27, 2020. doi:10.1200/JCO.2020.38.6_suppl.83

Next-generation sequencing identifies subtypes that may benefit from immune checkpoint inhibitors.

Alan H. Bryce, MD

Articles

Urologic implications of Lynch syndrome

How to approach immune checkpoint inhibitor therapy in prostate cancer