(UroToday.com) The 2023 ASCO annual meeting included a testicular cancer session, featuring a discussant presentation by Dr. Ben Tran discussing germinating data from germ cell tumors. Dr. Tran notes that testicular cancer is the most common cancer in young men, with long life expectancies secondary to the high cure rate because of cisplatin-based chemotherapy combinations. Importantly, a disease-free condition is not the equivalent of a life free of physical and psychosocial health problems. Particularly long lasting effects for testicular cancer patients can include cardiovascular disease, second malignancies, mental health issues, and a reduced life expectancy. Thus, research is focused on helping patients live longer and live better, minimizing treatment while maximizing outcomes.
The first abstract Dr. Tran discussed was “Molecular drivers of Organotropism and cisplatin resistance in germ cell tumors” by Dr. Aditya Bagrodia. This abstract asked the question of whether we can molecularly identify patients who will have cisplatin resistance, and will intensifying first line treatment in these patients maximize outcomes and minimize the need for salvage chemotherapy? Previously, Dr. Bagrodia’s group identified molecular features, including TP53 mutations and MDM2 amplification, associated with cisplatin resistance.1 In the current study, germ cell tumors (n = 138) were tested at Caris Life Sciences with next-generation sequencing of DNA (592-gene or whole exome) and RNA (whole transcriptome). A specialized genitourinary pathologist blindly reviewed selected H&E-stained slides and designated tumors as chemotherapy naïve (n = 66) or post-chemotherapy (n = 17) based on treatment related changes:
Dr. Tran notes that several limitations of this study include the limited clinical data, limited outcome data, and molecular associations with specimen type. Although there are several notable findings in this study, there is much work to do. Key findings included:
- KIT mutation more common in primary testicular cancer
- No difference in chemotherapy naïve versus post chemotherapy
- TP53 exclusively in metastasis
- No difference in platinum sensitivity score in NPV mutations
The Movember Foundation is helping a global effort to understand cisplatin resistance, led by Dr. Rob Hamilton from Princess Margaret Cancer Centre:
It is also important to identify those patients that are the very highest risk for recurrence, transitioning Dr. Tran to discuss the next abstract “Long term follow-up analysis of plasma miR371 expression to detect early relapse in patients with clinical stage I testicular germ cell tumors on surveillance” presented by Dr. Lucia Nappi. This study sought to answer several questions, including 1) Can we predict stage I patients who will recur? 2) Will adjuvant chemotherapy in these patients maximize outcomes and minimize need for chemotherapy at recurrence. In the current study, plasma miR371 was qualitatively assessed by RT-PCR. Sensitivity, specificity, negative and positive predictive values (NPV, PPV) and AUC in predicting tumor recurrence were evaluated in the post-orchiectomy blood samples and/or during the follow-up prior to or at the time of the clinically evident relapse. Additionally, relapse free survival was correlated to post-orchiectomy miR371 status. There were 298 patients queried, ultimately leading to 101 patients analyzed (36 nonseminoma, 65 seminoma):
In the entire cohort, the specificity and PPV were 100% (both 95% CI 94.5 - 100), sensitivity 62.8% (95% CI 44.9 - 78.5), NPV 83.5% (95% CI 76.7 - 88.6) and AUC 0.81 (95% CI 0.71 - 0.91). Dr. Tran notes that there were 7 miR371 negative “relapses”, 4 that were confirmed “not relapsed” by repeat imaging, 1 unnecessary RPLND for fibrosis, 1 second malignancy (lymphoma), and 1 true testicular cancer related relapsed but miR371 true negative (teratoma). Thus, discriminatory accuracy of miR371 can help avoid unnecessary biopsies/surgery/anxiety.
Dr. Tran also highlighted that the relapse free survival of the patients with positive post-orchiectomy miR371 was significantly shorter (median: 3.5 months vs. not reached; p<0.0001) compared to the patients with a negative post-orchiectomy miR371 (HR 16.95, 95% CI 2.11 - 135.7):
In the post-orchiectomy cohort, 15/68 (22%) experienced tumor relapse, with no false positives being observed. Over a median follow-up of 32 months, the specificity and PPV were 100% (both 95% CI 93.2 - 100), sensitivity 53.3% (95% CI 26.5 - 78.3), NPV 88.3% (95% CI 79.9 - 95.7) and AUC 0.76 (95% CI 0.60 - 0.93):
Dr. Tran notes that work remains to be done as a marker of minimal residual disease post-orchiectomy in a prospective fashion, which is highlighted by the three trials in progress that are currently being presented at this meeting:
There is also work to be done assessing which assay is best for clinical use: quantitative versus qualitative? Should we use serum versus plasma? Additionally, is increased sensitivity required? Threshold analyses suggest sensitivity for detection is 10 copies/uL, with post-orchiectomy miR-371 detecting 50% of recurrences (similar to ctDNA in stage 2 colon cancer).
Dr. Tran notes that the last topic of discussion is whether we can cure without chemotherapy or radiotherapy, leading to a discussion of “Primary RPLND in seminoma stage IIA-IIC ≤3cm: Combined results of the SWENOTECA (Swedish Norwegian Testicular Cancer Group) and Cologne” presented by Dr. Torgrim Tandstad. This study assessed whether primary RPLND is an acceptable alternative in stage 2 seminoma and whether we can cure patients without chemotherapy/radiotherapy and the associated long term toxicities. Importantly, late effects affecting mortality do not show up until 20+ years after diagnosis, specifically related to long-term toxicity. Dr. Tran emphasized that there has been an RPLND resurgence in stage 2 seminoma, highlighting the PRIMETEST trial, SEMS trial, and Royal Marsden trial:
In the SWENOTECA cohort, FDA PET is performed preoperatively, and if the PET is negative, this requires histological confirmation. In this study, primary unilateral RPLND resulted in 10 Clavien-Dindo > 2 complications. In high risk patients, BEP x 1 or BEP x 3 is suggested in high risk men, not carboplatin AUC7 x 1. Data from SWENOTECA and COTRIMS is summarized as follows:
Dr. Tran notes that primary RPLND is a standard of care alternative for stage 2 seminoma, but that short and long-term side effects need to be discussed and considered for these patients. Understanding health related quality of life impact from primary RPLND in the short/medium term is also important, and recurrence risks need to be discussed with the patient. Optimal patient selection (with perhaps miR-371, pre-operative imaging < 4 weeks from surgery, and use of FDG PET) may minimize recurrence risk and minimize unnecessary surgery. Finally, we should consider adjuvant chemotherapy (carboplatin vs BEP) in selected high risk patients.
Dr. Tran concluded his discussant presentation of these three testicular cancer abstracts, with the following pictorial take home point highlighting “germinating over germ cell data”:
Presented by: Ben Tran, MD, Peter MacCallum Cancer Centre, Melbourne, Australia
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.
References:
- Bagrodia A, Lee BH, Lee W, et al. Genetic determinants of cisplatin resistance in patients with advanced germ cell tumors. J Clin Oncol. 2016 Nov 20;34(33):4000-4007.