Introduction:

Lynch syndrome (LS) is an autosomal dominant familial pan-cancer syndrome caused by germline mutation in DNA mismatch repair genes, MLH1, MSH2, MSH6, PMS2. Despite being a rare cancer, upper tract urothelial carcinoma (UTUC) is the third most common LS-associated cancer. The clinical features and outcomes of patients with LS-associated UTUC remain poorly understood as many are not properly diagnosed at the point of care due to lack of universal tumor screening for mismatch repair protein deficiency or microsatellite instability, hallmarks of LS-associated cancer which qualify patients for immunotherapy. In addition to tumor testing, personal and family history of LS-associated cancers are screening criteria classically used to identify colorectal and endometrial cancer patients with LS. The objective of this study is to define the clinical features and outcomes of patients with personal or family history of LS-associated cancer to identify areas of improvement for Lpatients with UTUC. 

Methods:

This is a multicenter retrospective study of patients with UTUC who underwent radical nephroureterectomy at seven institutions from 02/2000 to 02/2021. All sites recorded the presence of personal or family history of LS-associated cancers and detailed clinicopathologic characteristics. Baseline clinical features were assessed by presence of history of LS-associated cancers (either personal or family history). Partial and complete response to neoadjuvant chemotherapy (NAC) were assessed by Lynch history status. In the adjuvant chemotherapy (AC) cohort, response was measured by metastatic recurrence and overall survival. Analysis was restricted to patients who received adequate chemotherapy (defined as at least 3 cycles) and those with pathologic and follow up data. Proportions of categorical variables were compared using the chi-squared test. Outcomes were compared using univariable logistic regression.

Results:

Of 2276 patients, 225 (10%) reported a personal or family history of LS-associated cancer. Baseline clinical characteristics of the total cohort and comparison between those with and without Lynch history are summarized in Table 1. Significant differences between those with Lynch history include younger age at diagnosis (p=0.0003), female gender (p<0.001), high grade (p=0.001), and multifocality (p=0.003). A total of 364 and 121 patients met inclusion criteria for NAC and AC analyses, respectively. Median length of follow up was 30 months (IQR 10 – 64) post-surgery. Factors that may be associated with lower complete and partial response in the NAC and higher risk of metastatic recurrence in the AC cohorts included history of Lynch, smoking history, and preoperative hydronephrosis whereas cisplatin-based chemotherapy may be associated with better outcomes (Table 2). 

Conclusion:

LS-related UTUC may have distinct biologic behavior and responses to chemotherapy than sporadic UTUC. Given the superior outcomes seen with immunotherapy in metastatic disease and the approved indication for this treatment in those with LS, proper identification of LS-related UTUC is imperative in order to evaluate this paradigm further in the non-metastatic setting. This can be most reliably achieved with universal tumor testing and confirmatory germline sequencing.

Funding: N/A