ASCO 2022: The Natural History and Genetics of Germ Cell Tumors - Discussion

(UroToday.com) The 2022 ASCO annual meeting featured an oral abstract session on testicular cancer, including a discussant presentation by Dr. Rahul Aggarwal discussing the natural history and genetics of germ cell tumors. For this discussant presentation, Dr. Aggarwal discussed two abstracts including “Late relapses in testicular cancer: Results from a national cohort” presented by Dr. Torgrim Tandstad and “Defining germline genetics of germ cell tumor: Implications for genetic testing and clinical management” presented by Dr. Hong Truong.

Late relapses in germ cell tumors is defined as recurrence > 2 years from initial treatment, in the absence of a new contralateral primary tumor. Furthermore, patterns of recurrence/prognosis differ based on stage of disease at presentation and prior chemotherapy: (i) for CS I, chemotherapy naïve patients have better outcomes, and (ii) for CS II/III, patients treated with initial chemotherapy may have teratoma +/- malignant transformation and chemotherapy-resistant yolk sac tumors, subsequently leading to worse outcomes. Current recommendations for surveillance according to the NCCN guidelines are to consider annual tumor markers + physical examination for years 5-10 in higher risk patients (ie. stage III NSGCT). When looking at the available literature, Dr. Aggarwal notes that the study from Norway by Dr. Tandstad assessing incidence of late relapse compares favorably to other studies:

 

ASCO 2022_Rahul R. Aggarwal_0 

 

 In the Norwegian study, a total of 472 patients experienced relapse, including 186 seminoma and 286 nonseminoma. Of these, 109 were late relapses (51 seminomas, 58 nonseminomas), 50 very late relapses (22 seminomas, 28 nonseminomas) with 17 relapses (4 seminomas, 13 nonseminomas) beyond ten years. Dr. Aggarwal highlighted that the incidence of late relapses beyond 5 years (ie. beyond the standard surveillance recommendations) was only 1.2% (67/5,712):

 

ASCO 2022_Rahul R. Aggarwal_1 

 

 There are several factors associated with survival of late relapse, including stage at diagnosis, prior chemotherapy exposure, surgical resection, and time interval from initial diagnosis to relapse. From the Norwegian study, late relapses after stage I disease at presentation have a favorable prognosis. Patients followed with surveillance (n = 1,380) had a higher rate of late relapses compared to patients receiving adjuvant therapy (n = 2,619) (4.0% vs 0.9%). A total of 8 deaths occurred in 61 patients with late relapse, including 4 from testicular cancer (3 nonseminoma and 1 seminoma). Historically, late relapses associated with prior chemotherapy exposure have worse survival outcomes:

 

ASCO 2022_Rahul R. Aggarwal_2 

 

Compared to other studies, the study from Tandstad et al. had a shorter median time to late relapse and a better 5-year survival from late relapse:

 

ASCO 2022_Rahul R. Aggarwal_3 

 

It is important to note that very late relapses (>5 years) are associated with worse survival, which may be secondary to chemotherapy resistance, multifocality, and/or viable tumor/teratoma with malignant transformation:

 

ASCO 2022_Rahul R. Aggarwal_4 

 

Dr. Aggarwal summarized this population-level study assessing late relapses by discussing if the results change clinical practice:

  • Routine surveillance beyond 5 years? Very late relapses are uncommon and consideration of annual tumor markers from years 5-10 in select patients (ie. stage III NSGCT) should remain the standard of care
  • Reconsideration of late relapses as a unique entity? Late relapses should remain defined entity, as very late relapses >5 years after prior chemotherapy clearly have worse outcomes. We should consider redefining relapse as a spectrum rather than early versus late relapses

 

Dr. Aggarwal then discussed germline mutations in patients with germ cell tumors, noting that testicular cancer has a higher than average heritability when compared to other malignancies, as highlighted in the following figure:

 

ASCO 2022_Rahul R. Aggarwal_5 

 

 Genome-wide association studies partially explain high heritability of tumors. Previous work has suggested that 78 susceptible loci in the genome have been identified accounting for 44% of known heritability. Polygenic risk scores created based on these gene loci suggest that patients may have up to a 6.8-fold increased risk of testicular cancer compared to the median. Thus, the lifetime risk for someone with a high polygenic risk score is 3.4% vs 0.4% in the general population. Previously, AlDubabyan et al.1 sought to systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DNA repair gene alterations in patients with testicular germ cell tumors vs healthy controls. This study was a case-control enrichment analysis to screen for 48 DNA repair gene alterations in 205 unselected men with testicular germ cell tumors and 27,173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort. This study found that unselected men with testicular germ cell tumors were approximately 4 times more likely to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals (OR 3.87, 95% CI 1.65-8.86):

 

ASCO 2022_Rahul R. Aggarwal_6 

 

The MSKCC cohort presented today demonstrates concordant results with regards to DNA pathway genes, noting DNA damage repair gene alteration in 44 cases (9%) and low loss of heterozygosity (28%). Furthermore, primary mediastinal germ cell tumors may be enriched for pathogenic germline mutations, with higher TP53 alterations:

 

ASCO 2022_Rahul R. Aggarwal_7 

 

 

Dr. Aggarwal summarized this study assessing genetic alterations in patients with germ cell tumors by discussing if the results change clinical practice:

  • Routine germline testing in germ cell tumors? Probably not in all patients, but it may be reasonable to consider in patients with mediastinal germ cell tumors. Validation using real-world data including diverse patient populations is essential
  • Therapeutic decision making? There is low frequency of loss of heterozygosity and thus a lack of targetable alterations, and therefore unlikely to impact management of germ cell tumor patients


Presented by: Rahul R. Aggarwal, MD, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022.

References:

  1. AlDubayan SH, Pyle LC, Gamulin M, et al. Association of inherited pathogenic variants in Checkpoint Kinase 2 (CHEK2) with susceptibility to testicular germ cell tumors. JAMA Oncol. 2019 Apr 1;5(4):514-522.

 

email news signup