Without established guidelines for Lynch-syndrome-associated upper tract urothelial cancer (UTUC), patients who carry germline mutations in related genes are under-recognized and at risk for not receiving the care they need.
Hong Truong, MD, serves as a co-investigator of a recent study that defines selection criteria for patients with UTUC for Lynch syndrome screening.1 In this interview, she discusses the findings of this study and how they are important for not only diagnosing and managing the patients with Lynch-syndrome-associated UTUC, but also for their families who may similarly carry mutations. She presented the study recently at the 2022 ASCO Genitourinary Cancers Symposium. Dr. Truong is a urologic oncology fellow at Memorial Sloan Kettering Cancer Center in New York, New York.
Lynch Syndrome is an autosomal dominant and highly penetrant disorder caused by germline mutations of DNA mismatch repair genes (commonly called MMR genes). Lynch syndrome represents the most common hereditary cause of colorectal cancer. It also predisposes to other extracolonic tumors such as endometrial, upper tract urothelial carcinoma, and gastric, ovarian cancer etc. Despite being a relatively rare cancer, upper tract urothelial carcinoma ranks third most common among Lynch syndrome-associated cancers. Lynch syndrome increases the risk of upper tract cancer by 22 fold compared to the general population.
Urologists play a critical role in identifying patients with upper tract cancer who may be at risk of having Lynch syndrome and refer those patients for genetic counseling and testing. However, there is no current national guideline to evaluate for Lynch syndrome in patients with upper tract cancer. The NCCN guideline, which uses the revised Bethesda guideline, targets patients with colorectal and endometrial cancers. Interestingly, the guideline calls for germline testing for patients with MMR deficient tumor, yet, upper tract tumor is not routinely tested for MMR protein status.
There are important knowledge gaps in the management of patients with upper tract cancer. Namely, there is no guideline to assist in the evaluation of Lynch syndrome in patients with UTUC. The frequency and spectrum of germline mutations in patients with UTUC are unknown
Patients with hereditary upper tract cancer may be under recognized and under referred for genetic evaluation.
The objective of my study was to define selection criteria for patients with UTUC for Lynch syndrome screening. To answer this question, we did an in depth review and analysis of 232 patients with upper tract cancer who underwent matched tumor and germline sequencing at Memorial Sloan Kettering. My co-author, Rania Sheikh, who is a genetic counselor and I reviewed every chart for patient cancer and family history and determine whether or not patients would have qualified for Lynch syndrome testing based on current NCCN guideline. Dr. Hikmat Al Ahmadie, who is a GU pathologist, performed immunohistochemical staining for MMR proteins on upper tract tumors of patients when available.
First of all, we found [that] 16% of patients with upper tract cancer had germline pathogenic, or likely pathogenic, mutations. Of these [patients], 9% had a germline variant in a mismatch repair gene which is a gene that's associated with Lynch syndrome. An additional 6% had germline variants in other DNA damage repair genes. A total of about 13% of the patients have a germline variant in a high-risk cancer predisposition gene, which is a pretty high number. We found that the most common MMR gene variant in patients with upper tract cancer is MSH2, followed by MLH1 and MSH6. We also identified some BRCA1 and [BRCA2] germline mutations in our cohort. Most important, though, is the clinical and pathologic factors associated with the presence of MMR variants. We found that patients who have upper tract cancer diagnosed before the age of 65 have higher prevalence of MMR variants. We chose the cutoff of 65 because the European Association of Urology’s guideline on upper tract cancer have suggested that patients with upper tract [cancer] diagnosed before the age of 65 may have more incidence of Lynch syndrome, and we confirmed that to be true.
We found that while the NCCN guideline for Lynch syndrome is highly specific in identifying patients with Lynch syndrome, it missed about 50% of patients with upper tract cancer who had Lynch syndrome. Likewise, personal history of having a Lynch-syndrome-associated cancer or family history of having a Lynch-syndrome-associated cancer are not sensitive, although they are associated with the diagnosis of Lynch syndrome in patients with upper tract cancer. The most sensitive criteria in identifying patients with Lynch-syndrome-associated upper tract cancer is MMR deficient tumors. 94% of patients who have MMR deficient tumors were found to have germline mutations in MMR genes. Sixty-seven percent of patients with [microsatellite instability (MSI)] high tumors [were] also found to have an MMR gene variant. What all that means is that the current family history- or personal history-based criteria that's geared toward endometrial and colorectal cancer missed essentially 50% of patients with hereditary upper tract cancer, so we need better guidelines specifically for patient with Lynch-syndrome-associated upper tract cancer. One thing that may be slightly surprising for us is [that] 50% of patients with germline mutations in MMR genes had upper tract cancer as their first cancer diagnosis. Even though patients with Lynch syndrome may develop recurrent and bilateral upper tract cancer, only the 3 out of 21 patients, or 14% in our cohort, had bilateral UTUC, so you can't really use this as a screening criterion because you would otherwise miss a lot of patients.
The immediate impact is [that] upper tract tumors need to be stained for MMR proteins, just like the way that colorectal and endometrial cancer are being tested right now, when the tumor is available. I believe ovarian and gastric cancers are also tested for the same thing, but surprisingly not as [many] upper tract tumors are assessed. This approach has two important implications in patient management . Number one is it helped to identify patients who [are] at risk for Lynch syndrome and who need to be referred for genetic testing. The second implication is in patients with advanced disease, they may qualify for immunotherapy, something that we don't routinely use in upper tract. So, that will impact patient care directly. The study also showed how important it is to [get] a detailed personal and family history when patients come in for evaluation. Even though we [can] see patients [only] for upper tract tumors, we should be aware that there are other multi-systemic features that would identify a patient who may be at risk for hereditary cancer syndromes.
This is only the tip of the iceberg, right? I think we're only starting to understand that, yes, hereditary upper tract cancer is an entity, and we need to identify the patient, but we don't understand the biology of the tumors, we don't understand the pathogenesis of the tumors, we don't know how these patients should be managed. So, there are a lot of unresolved questions. Immediately, within my cohort of patients, I'm looking [at those] with bilateral upper tract tumors [for] what the concordance of MMR protein deficiency and MSI high status is? [How can I understand] the biology of patients who develop bilateral upper tract cancer? In upper tract tumors, there's not a lot of tissue for initial diagnosis. A lot of the time we diagnose based on cytology, so how do we determine tumor MMR protein status based on cytology? Does that involve single-cell sequencing or next-generation sequencing? Those are some of the criteria that we need to develop better workflow [for] and a way to [do] tissue testing in patients with upper tract [cancer].
Practicing urologists play a critical role, and they're essentially the first checkpoint in identifying patients with potentially hereditary upper tract cancer. They need to know that the prevalence of Lynch syndrome among patients [with] upper tract cancer is high, and there needs to be an awareness that half of patients may present with upper tract as their only cancer diagnosis. Historically, [we're] thinking about patients who already have colorectal cancer [or] endometrial cancer, but that's not necessarily the case. So, having a high index of suspicion and sending patients for genetic counseling and germline testing is important. That makes a huge difference in not just patient management, but also for their family members. [The] enhanced cancer screening and surveillance for the patients may change their management approach. So, for instance, [in] patients with hereditary upper tract cancer, radical nephroureterectomy for high-grade cancer may not be an ideal approach because they tend to develop recurrence in the contralateral collecting system. For the at-risk family member who didn't have prior diagnosis of Lynch syndrome, they would qualify for germline testing, and that also affects their cancer screening and surveillance.
The management of hereditary upper tract cancer and Lynch syndrome [is] a multidisciplinary approach. I think [that] in order to better take care of these patients, there should be a consensus among not just urologists, but GU pathologists and medical oncologists. There's a dire need for a guideline for patients with upper tract cancer, and I think it should involve MMR testing and MSI status testing for all patients with upper tract cancer. That's from the pathology side. There's also [the] need for involvement of [a] genetic counselor in seeing patients with upper tract urothelial carcinoma. In medical oncology, I think there's room for clinical trials to explore new systemic regimen as we identify more patients with upper tract cancer who had MMR deficient tumors, Lynch syndrome, or MSI high tumors.
1. Truong H, Sheikh R, Kemel Y, et al. Defining hereditary upper tract urothelial carcinoma: Implications for genetic testing and clinical management. Paper presented at: 2022 ASCO Genitourinary Cancers Symposium; February 17-19, 2022; San Francisco, California. Abstract #523