Purpose:

The prevalence and clinical characteristics of small bowel adenocarcinomas (SBA) in the setting of Lynch syndrome have not been well studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes.

Experimental Design:

A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via IHC staining. Germline DNA was analyzed for mutations in known cancer predisposition genes, including MMR (MLH1, MSH2, MSH6, PMS2, and EPCAM). Clinical variables were correlated with MMR/MSI status.

Results:

Twenty-six percent (26/100; 95% confidence interval, 18.4–35.4) of SBAs exhibited MMR deficiency (MMR-D). Lynch syndrome prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-Lynch syndrome MMR-D versus MMR-proficient (MMR-P) SBAs (65 vs. 61; P = 0.75), but significantly younger in Lynch syndrome (47.5 vs. 61; P = 0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P versus 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in Lynch syndrome (P = 0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared with 23.1% (6/26) in the MMR-D group (P = 0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared with 18.2% (2/11) in the MMR-D group (P = 0.0002).

Conclusions:

When compared with MMR-P SBA, MMR-D SBA was associated with earlier stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline Lynch syndrome testing in MMR-D SBA is warranted.

Translational Relevance

Small bowel adenocarcinoma (SBA) is a rare, aggressive cancer known to be associated with Lynch syndrome. Clinical management guidelines for SBA have historically been extrapolated from those of colorectal cancer. Our study systematically characterized SBA according to mismatch repair (MMR) and Lynch syndrome status. Our data show that one-fourth of SBAs were MMR deficient (MMR-D) with nearly 40% of patients with MMR-D tumors having Lynch syndrome. Patients with MMR-D SBA were more likely to have early-stage disease and lower recurrence rates. Assessment of all SBAs for MMR deficiency with recognition of better prognosis and potential futility of chemotherapy in early-stage MMR-D SBAs has immediate clinical implications. Moreover, 50% of patients with Lynch syndrome presented with SBA as their index cancer and would not have been identified as having Lynch syndrome had they not undergone MMR assessment, which not only has direct implications for patients, but also their at-risk family members.

Small bowel adenocarcinoma (SBA) is a rare, aggressive cancer, accounting for only 0.6% of new cancer diagnoses in the United States in 2019 (1), with approximately two-thirds diagnosed at advanced stages (1, 2). Given its rarity, clinical recommendations were historically based on colorectal cancer guidelines. However, when compared with colorectal cancer, SBA is more aggressive with inferior outcomes at all stages (2–5). Research has recently emerged suggesting that colorectal cancer and SBA may be more physiologically and molecularly distinct than once thought (2–4, 6), with most studies focusing on tumor molecular profiling, adenoma to carcinoma transformation, and tumor histologic grade (2–4, 6). Importantly, the unique genomic landscape of SBA as compared with other gastrointestinal (GI) malignancies was elegantly demonstrated in a recent study (6), but the resultant impact on clinical treatment outcomes has not been well described. Given the increased recognition of the distinct nature of SBA, in 2020 the clinical committee of the National Comprehensive Cancer Center (NCCN) established separate guidelines for the diagnosis and management of SBA from colorectal cancer. While adjuvant treatment recommendations mimic those in colorectal cancer, there are some differences noted in the metastatic setting, such as the recommendation against anti-EGFR treatments for RAS wild-type SBA given the lack of demonstrated benefit (7). However, other clinical guidelines, like the European Society for Medical Oncology, have not yet pursued independent recommendations for SBA.

It has been well established in early-stage colorectal cancer that tumors demonstrating DNA mismatch repair deficiency and/or microsatellite instability (MMR-D/MSI) have a favorable prognosis compared with MMR-proficient/microsatellite stable (MMR-P/MSS) tumors (8–11). Furthermore, patients with MMR-D colorectal cancer appear to lack clinical benefit from adjuvant 5-fluorouracil (5-FU)-based chemotherapy compared with MMR-P colorectal cancer, allowing for surgical management alone for early-stage (II) disease (8–10). Given this, and the fact that 3% of colorectal cancers are due to Lynch syndrome (12), universal screening of all colorectal cancers for MMR-D status is currently standard of care (13). While these observations in colorectal cancer have been extrapolated to SBA, there are currently limited studies assessing the prognostic value of MMR-D status in SBA (14), and no studies directly comparing clinical treatment response with that of MMR-P SBA. Moreover, with the FDA approval of pembrolizumab therapy for all advanced MMR-D solid tumors, MMR-D analysis is now being increasingly incorporated into the care of all patients with advanced cancer, including those with SBA (15).

We have previously demonstrated that MMR-D/MSI status is associated with Lynch syndrome pan-cancer (16). Lynch syndrome is an autosomal-dominant cancer predisposition syndrome with up to an 80% lifetime risk of cancer development of multiple types, requiring life-long surveillance (12, 17, 18). Patients with Lynch syndrome harbor germline mutations in the MMR genes (MLH1, MSH2, MSH6, PMS2, and EPCAM; refs. 12, 19). As SBA is a rare, but known Lynch syndrome–associated tumor (16, 20, 21), we sought to characterize SBA according to MMR and germline mutation status and compare clinical outcomes.

Study population

The study comprised patients diagnosed with primary SBA, in which MSI and/or MMR-D assessment was ordered at Memorial Sloan Kettering Cancer Center (New York, NY) from 2006 to 2019. This study was conducted in accordance with the recognized ethical guidelines of the U.S. Common Rule. Included patients provided written informed consent to either the institutional review board (IRB)-approved protocol for matched tumor/normal DNA sequencing via MSK-IMPACT (ClinicalTrials.gov identifier, NCT01775072) or to an IRB-approved protocol for prospective tracking of MMR-D tumors and/or biospecimen collection. Patient electronic medical records were reviewed. While 111 unique patients were identified as having small bowel tumors, only those with pathology confirmed primary SBA were included in this analysis (n = 100). Of the 11 excluded cases, 4 patients were found to have ampullary cancers of pancreatic origin, three were neuroendocrine tumors, three were colorectal cancer metastases, and one was a gastric cancer (signet ring cell) metastasis. Of our total cohort (N = 100), 2 patients did not have MSI or MMR-D testing, as one canceled the test request and the other had inadequate tissue available for MSI analysis.

MSI analysis and IHC staining

Beginning in 2014, our institution adopted universal IHC for MMR proteins (and/or MSI) on all colorectal cancers and endometrial tumors, with our much smaller numbers of SBAs also routinely undergoing such analysis. Inclusion of next-generation sequencing (NGS) MSI assessment in the research setting began in 2016. Prior to 2014, our institution only routinely assessed MMR status in SBA diagnosed under 50 years of age. For MSK-IMPACT–sequenced tumors, MSI assessment was conducted using MSIsensor, a NGS-based bioinformatics platform that incorporates data from more than 1,000 microsatellite regions, reporting the percentage of unstable loci as a cumulative score (22, 23). MSIsensor scores ≥10 designate high (MSI-H) status, scores ≥3–<10 an indeterminate (MSI-I) status, and scores <3 MSS (16, 22, 23). MSK-IMPACT is approved by the NYS Department of Health (New York, NY) for clinical use and authorized by the FDA for clinical reporting of somatic mutations, indels, rearrangements, and MSI calculated from the microsatellite regions covered by the assay (22–26).

IHC staining for DNA MMR protein expression was performed using standard procedures (27) and compared with tumor MSIsensor scores to establish concordance rates. A tumor was considered IHC/MSI concordant if the MSIsensor score was ≥3 and the IHC result demonstrated lack of MMR protein expression. For the purposes of simplification, MMR-D refers to MMR deficiency demonstrated either via IHC or MSI via MSIsensor.

Germline analysis

In patients with known Lynch syndrome, genetic testing reports were reviewed to confirm diagnoses. For patients who underwent MSK-IMPACT germline assessment, DNA extracted from peripheral blood was used for analysis of up to 88 known cancer predisposition genes, including MMR genes (MLH1, MSH2, MSH6, PMS2, and EPCAM). Only deletions/rearrangements involving the 3′ region of EPCAM, causative of Lynch syndrome, were considered (28, 29). Single-exon and PMS2 deletions that encompassed exons 13 and 14 were only included if confirmed by orthogonal method, given the presence of known pseudogenes, as per standard operating procedures. Variant calling was performed in accordance with the American College of Medical Genetics and Genomics (Bethesda, MD) variant classification standards (26, 30). All research-based genetic testing was confirmed with clinical grade testing in a Clinical Laboratory Improvement Amendments–approved laboratory. Only patients with pathogenic or likely pathogenic variants were considered germline positive.

Statistical analysis

Continuous variables were compared using either a two-tailed t test or a Mann–Whitney U-test, as appropriate. Categorical variables were compared using either a χ2 or Fisher exact test, depending on sample size. P < 0.05 was considered statistically significant.

Lynch syndrome prevalence

We identified that the prevalence of MMR-D was 26% [26/100; 95% confidence interval (CI), 18.4–35.4], with most MMR-D tumors (65.4%; 17/26) demonstrating loss of expression of MLH1 and/or PMS2 proteins on IHC. A total of 15.4% (4/26) of MMR-D tumors demonstrated loss of MSH2/MSH6 protein expression. The overall Lynch syndrome prevalence in our SBAs was 10% (10/100), with all Lynch syndrome–associated cases exhibiting MMR-D. When assessing Lynch syndrome prevalence in MMR-D SBA, 38.5% (10/26; 95% CI, 22.4–57.5) had Lynch syndrome (Fig. 1A). In comparison, among 826 patients with colorectal cancer included in our prior study (16), 16.6% (137) of tumors exhibited MMR-D; of these, 19% (26/137) were found to have Lynch syndrome (ref. 16; Fig. 1B; P = 0.002). Of our 10 patients with SBA with Lynch syndrome, the distribution of germline mutations was 50% (5/10) in MLH1, 30% (3/10) MSH2, and 20% (2/10) PMS2 (Fig. 2).

Figure 1.

Prevalence of MMR-D and Lynch syndrome (LS) in SBA compared with colorectal cancer. A, MMR-D and Lynch syndrome prevalence in SBA. Pie chart demonstrates that 26% (26/100) of SBAs were found to be MMR-D. Of the MMR-D cases, 38.5% (10/26) of patients had underlying Lynch syndrome, as indicated by top portion of bar graph. Panel B: MMR-D and Lynch syndrome prevalence in colorectal cancer from our prior study (Latham and colleagues, 2019; ref. 16). Pie chart demonstrates that 83.4% (689/826) of colorectal cancers were found to be MMR-P, while 16.6% (137/826) of colorectal cancers were found to be MMR-D. Of the MMR-D cases, 19% (26/137) of patients had underlying Lynch syndrome, as indicated by top portion of bar graph.

Figure 1.

Prevalence of MMR-D and Lynch syndrome (LS) in SBA compared with colorectal cancer. A, MMR-D and Lynch syndrome prevalence in SBA. Pie chart demonstrates that 26% (26/100) of SBAs were found to be MMR-D. Of the MMR-D cases, 38.5% (10/26) of patients had underlying Lynch syndrome, as indicated by top portion of bar graph. Panel B: MMR-D and Lynch syndrome prevalence in colorectal cancer from our prior study (Latham and colleagues, 2019; ref. 16). Pie chart demonstrates that 83.4% (689/826) of colorectal cancers were found to be MMR-P, while 16.6% (137/826) of colorectal cancers were found to be MMR-D. Of the MMR-D cases, 19% (26/137) of patients had underlying Lynch syndrome, as indicated by top portion of bar graph.

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Figure 2.

Distribution of MMR gene mutations in MMR-D SBA. MMR genes are listed on the x-axis. Percentage of mutations per gene is indicated on the y-axis. A total of 50% (5/10) of germline mutations were found in the MLH1 gene, 30% (3/10) of germline mutations were found in MSH2, and 20% (2/10) in PMS2. There were no underlying MSH6 or EPCAM germline mutations. **, One patient with germline MSH2 mutation was also found to harbor germline NTHL1 mutation.

Figure 2.

Distribution of MMR gene mutations in MMR-D SBA. MMR genes are listed on the x-axis. Percentage of mutations per gene is indicated on the y-axis. A total of 50% (5/10) of germline mutations were found in the MLH1 gene, 30% (3/10) of germline mutations were found in MSH2, and 20% (2/10) in PMS2. There were no underlying MSH6 or EPCAM germline mutations. **, One patient with germline MSH2 mutation was also found to harbor germline NTHL1 mutation.

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The prevalence of MMR-D after the adoption of routine MMR-D assessment in SBA in 2014, was 25%, equivalent to the overall cohort MMR-D prevalence.

Patient and tumor characteristics

Of the 100 patients with SBA, 95% had clinical information available for review. Five were consult-only patients referred to our tertiary center without additional clinical follow-up. Two did not have MSI or IHC analysis conducted on their tumors, and there was no additional tumor available to complete these assays. As such, there were 93 patients for whom demographic, clinical, and tumor pathology data were available for review. Patient demographics and clinical characteristics are demonstrated in Table 1.

Table 1.

Patient clinical characteristics.

CharacteristicTotal cohort (N = 100)aMMR-P (n = 72)bMMR-D non-LS (n = 16)MMR-D + LS (n = 10)
Median age at SBA diagnosis 60 60 65 47.5 
Male 62% (59) 65.7% (44) 50% (8) 50% (5) 
Female 38% (36) 34.3% (23) 50% (8) 50% (5) 
Race/ethnicity 
 Non-Hispanic White 74.7% (70) 73.1% (49) 75% (12) 80% (8) 
 Non-Hispanic Black 10.5% (10) 11.9% (8) 6.3% (1) 10% (1) 
 Asian 6.3% (6) 4.5% (3) 12.5% (2) 10% (1) 
 Hispanic 4.2% (4) 4.5% (3) 6.3% (1) 0% 
 Patient declined to answer 5.3% (5) 6% (4) 0% 0% 
Positive smoking history 43.2% (41) 40.3% (27) 37.5% (6) 60% (6) 
Tumor location 
 Duodenum 41% (41) 38.9% (28) 43.8% (7) 50% (5) 
 Jejunum 39% (39) 36.1% (26) 53.3% (9) 30% (3) 
 Ileum 18% (18) 22.2% (16) 0% 20% (2) 
 Small bowel, NOS 2% (2) 2.8% (2) 0% 0% 
Tumor differentiation on pathology 
 Well-differentiated 2% (2) 2.8% (2) 0% 0% 
 Moderately differentiated 44% (44) 43.1% (31) 25% (4) 70% (7) 
 Poorly differentiated 45% (45) 41.7% (30) 75% (12) 30% (3) 
 Unknown 9% (9) 12.5% (9) 0% 0% 
SBA as index cancer 82% (78) 86.6% (58) 93.8% (15) 50% (5) 
Synchronous/metachronous tumors 15.8% (15) 9% (6) 18.8% (3) 60% (6) 
Stage at diagnosis 
 Stage I 4.2% (4) 1.5% (1) 0% 30% (3) 
 Stage II 25.2% (24) 23.9% (16) 25% (4) 40% (4) 
 Stage III 23.2% (22) 19.4% (13) 43.8% (7) 20% (2) 
 Stage IV (metastatic) 45.3% (43) 52.2% (35) 31.3% (5) 10% (1) 
 Unknown 2.1% (2) 3% (2) 0% 0% 
Median LN dissected (range)c 11(1–77) 10 (1–77) 14 (2–27) 22 (5–39) 
Median positive LN (range)c 0(0–15) 1 (0–15) 1 (0–7) 0 (0–4) 
Initial treatment 
 Surgery alone 11.6% (11) 6% (4) 12.5% (2) 50% (5) 
 Chemotherapy 73.7% (70) 83.6% (56) 68.8% (10) 20% (2) 
 Chemo + immunotherapy 6.3% (6) 1.5% (1) 12.5% (2) 30% (3) 
 X-ray therapy alone 1.1% (1) 1.5% (1) 0% 0% 
 Declined/palliation 2.1% (2) 3% (2) 0% 0% 
 Unknown or treated elsewhered 5.3% (5) 4.5% (3) 12.5% (2) 0% 
Recurrence in early stage (I/II) 17.9%(17) 88.2%(15) 25%(1) 14.3%(1) 
CharacteristicTotal cohort (N = 100)aMMR-P (n = 72)bMMR-D non-LS (n = 16)MMR-D + LS (n = 10)
Median age at SBA diagnosis 60 60 65 47.5 
Male 62% (59) 65.7% (44) 50% (8) 50% (5) 
Female 38% (36) 34.3% (23) 50% (8) 50% (5) 
Race/ethnicity 
 Non-Hispanic White 74.7% (70) 73.1% (49) 75% (12) 80% (8) 
 Non-Hispanic Black 10.5% (10) 11.9% (8) 6.3% (1) 10% (1) 
 Asian 6.3% (6) 4.5% (3) 12.5% (2) 10% (1) 
 Hispanic 4.2% (4) 4.5% (3) 6.3% (1) 0% 
 Patient declined to answer 5.3% (5) 6% (4) 0% 0% 
Positive smoking history 43.2% (41) 40.3% (27) 37.5% (6) 60% (6) 
Tumor location 
 Duodenum 41% (41) 38.9% (28) 43.8% (7) 50% (5) 
 Jejunum 39% (39) 36.1% (26) 53.3% (9) 30% (3) 
 Ileum 18% (18) 22.2% (16) 0% 20% (2) 
 Small bowel, NOS 2% (2) 2.8% (2) 0% 0% 
Tumor differentiation on pathology 
 Well-differentiated 2% (2) 2.8% (2) 0% 0% 
 Moderately differentiated 44% (44) 43.1% (31) 25% (4) 70% (7) 
 Poorly differentiated 45% (45) 41.7% (30) 75% (12) 30% (3) 
 Unknown 9% (9) 12.5% (9) 0% 0% 
SBA as index cancer 82% (78) 86.6% (58) 93.8% (15) 50% (5) 
Synchronous/metachronous tumors 15.8% (15) 9% (6) 18.8% (3) 60% (6) 
Stage at diagnosis 
 Stage I 4.2% (4) 1.5% (1) 0% 30% (3) 
 Stage II 25.2% (24) 23.9% (16) 25% (4) 40% (4) 
 Stage III 23.2% (22) 19.4% (13) 43.8% (7) 20% (2) 
 Stage IV (metastatic) 45.3% (43) 52.2% (35) 31.3% (5) 10% (1) 
 Unknown 2.1% (2) 3% (2) 0% 0% 
Median LN dissected (range)c 11(1–77) 10 (1–77) 14 (2–27) 22 (5–39) 
Median positive LN (range)c 0(0–15) 1 (0–15) 1 (0–7) 0 (0–4) 
Initial treatment 
 Surgery alone 11.6% (11) 6% (4) 12.5% (2) 50% (5) 
 Chemotherapy 73.7% (70) 83.6% (56) 68.8% (10) 20% (2) 
 Chemo + immunotherapy 6.3% (6) 1.5% (1) 12.5% (2) 30% (3) 
 X-ray therapy alone 1.1% (1) 1.5% (1) 0% 0% 
 Declined/palliation 2.1% (2) 3% (2) 0% 0% 
 Unknown or treated elsewhered 5.3% (5) 4.5% (3) 12.5% (2) 0% 
Recurrence in early stage (I/II) 17.9%(17) 88.2%(15) 25%(1) 14.3%(1) 

Abbreviation: LS, Lynch syndrome.

aThere were 2 patients in which MMR/MSI status was unknown, but demographic, clinical staging, and tumor histology are represented as part of overall cohort.

bFive MMR-P/MSS tumors had limited clinical information, but some demographic, tumor pathology, TNM staging, and tumor grade data are represented.

cA total of 68 patients underwent surgery, with 4 patients (three in MMR-P and one in non-LS MMR-D group) at outside institution and LN yield and positivity were not available.

dOne MMR-D/MSI non-LS patient on randomized controlled trial for pembrolizumab: unknown whether in treatment or placebo group, and was therefore counted as “unknown.”

While there was not a significant difference in median age of diagnosis between the MMR-proficient (MMR-P) and non-Lynch syndrome–associated MMR-D groups (60 and 65 years, respectively), Lynch syndrome–associated SBA was diagnosed in significantly younger patients, at a median age of 47.5 years (P = 0.03). Despite the earlier age of SBA onset in Lynch syndrome, 50% (5/10) had prior cancer, while the majority of MSS and sporadic MMR-D groups (86.6% and 93.8%, respectively) were diagnosed with SBA as their index cancer (P = 0.007; Table 1).

We assessed the prevalence of synchronous and/or metachronous cancers. We considered any primary cancer detected within 2 months of the SBA diagnosis as synchronous, whereas subsequent primary cancers (detected >2 months post-SBA diagnosis) were metachronous, in accordance with the Surveillance Epidemiology and End Results database (31). Among patients in the MMR-P group, 9% (6/67) had synchronous and/or metachronous cancers, compared with 34.6% (9/26) in the MMR-D group, with 66.7% (6/9) of these occurring in Lynch syndrome (P = 0.0002; Table 1). The majority of these tumors (60%; 9/15) were other primary GI cancers (synchronous SBA, colorectal cancer, and gastric), whereas additional endometrial and urothelial tumors were also identified among patients with Lynch syndrome.

Of the entire SBA cohort, 41% of tumors were located in the duodenum, 39% in the jejunum, and 18% in the ileum. There was no statistically significant difference in tumor location when compared across groups. Among Lynch syndrome, 50% (5/10) were located in the duodenum, compared with 38.9% (28/72) and 43.8% (7/16) in the MMR-P and MMR-D non-Lynch syndrome groups, respectively (P = 0.77; Fig. 3).

Figure 3.

Distribution of tumors by location, MMR, and Lynch syndrome (LS) status. Tumor location is indicated on the x-axis (duodenum, jejunum, ileum, and small bowel, NOS). Number of tumors per location is indicated on the y-axis, with largest number of tumors located in the duodenum. Each bar is subdivided by group as indicated. MMR-D non-LS, MMR-D without underlying Lynch syndrome.

Figure 3.

Distribution of tumors by location, MMR, and Lynch syndrome (LS) status. Tumor location is indicated on the x-axis (duodenum, jejunum, ileum, and small bowel, NOS). Number of tumors per location is indicated on the y-axis, with largest number of tumors located in the duodenum. Each bar is subdivided by group as indicated. MMR-D non-LS, MMR-D without underlying Lynch syndrome.

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As lymph node (LN) positivity informs treatment decisions, we assessed LN dissection among patients that underwent surgical resection, comparing total LNs resected and LN positivity across groups (Table 1). There were 4 patients that underwent surgery at an outside institution and LN yield and positivity were not available. Among MMR-P tumors, median LN yield was 10 (range, 1–77), with a median number of LNs positive for malignancy of one (range, 0–15). There was no difference when compared with the MMR-D group overall, where median LN yield was 14 (range, 2–39), with a median number of positive Lynch syndromes of 0 (range, 0–7; MMR-P vs. MMR-D LN yield; P = 0.07 and MMR-P %LN positive vs. MMR-D %LN positive; P = 0.32). In addition, we compared LN positivity across all three groups, and found that 50% (23/46) of MMR-P cases were LN positive, compared with 58.3% (7/12) and 11.1% (1/9) in our non-Lynch syndrome MMR-D and Lynch syndrome–associated SBA surgical cases, respectively, but this did not reach statistical significance (P = 0.066).

We also assessed tumor differentiation, as prior studies suggest that MMR-D colorectal cancers have a propensity toward poorly differentiated histology, partially driven by the more frequent presence of medullary carcinoma subtype (10, 32). While we noted that the majority of MMR-D tumors were poorly differentiated (57.7%; 15/26), histology was not statistically different when compared with the MMR-P group overall (Table 1; Fig. 4A). However, when assessing nonmetastatic disease alone, there was a difference in tumor differentiation, with 60% (12/20) of MMR-D tumors being poorly differentiated compared with 30% (9/30) in the MMR-P group (P = 0.03), consistent with prior observations in colorectal cancer (Fig. 4B; ref. 32).

Figure 4.

Tumor differentiation by MMR and LS status. A, Bar graph representing entire cohort in which MMR status available (both early and metastatic disease). Tumor differentiation indicated by grayscale spectrum with black representing well-differentiated tumors, dark gray moderately differentiated, medium gray poorly differentiated, and light gray as unknown. B, Bar graph representing non-metastatic cohort in which MMR status available. Tumor differentiation indicated by grayscale spectrum with black representing well-differentiated tumors, dark gray moderately differentiated, medium gray poorly differentiated, and light gray as unknown. Figure demonstrates that while no differences noted in histology overall, when assessing non-metastatic cases, MMR-D tumors were of predominately poorly-differentiated histology. MMR-P, mismatch repair proficient; MMR-D non-LS, mismatch repair deficient without underlying Lynch syndrome; LS, Lynch syndrome.

Figure 4.

Tumor differentiation by MMR and LS status. A, Bar graph representing entire cohort in which MMR status available (both early and metastatic disease). Tumor differentiation indicated by grayscale spectrum with black representing well-differentiated tumors, dark gray moderately differentiated, medium gray poorly differentiated, and light gray as unknown. B, Bar graph representing non-metastatic cohort in which MMR status available. Tumor differentiation indicated by grayscale spectrum with black representing well-differentiated tumors, dark gray moderately differentiated, medium gray poorly differentiated, and light gray as unknown. Figure demonstrates that while no differences noted in histology overall, when assessing non-metastatic cases, MMR-D tumors were of predominately poorly-differentiated histology. MMR-P, mismatch repair proficient; MMR-D non-LS, mismatch repair deficient without underlying Lynch syndrome; LS, Lynch syndrome.

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Patient clinical outcomes

In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared with 23.1% (6/26) in the MMR-D group (P = 0.008). Among early-stage (I/II) MMR-P SBA, 88.2% (15/17) recurred, compared with 18.2% (2/11) in the MMR-D group (P = 0.0002). When assessing the entire cohort, there was no statistically significant difference in the proportion of patients receiving systemic chemotherapy. A total of 85.1% (57/67) of the MMR-P group received either neoadjuvant or adjuvant chemotherapy at initial diagnosis, compared with 65.4% (17/26) in the MMR-D group (P = 0.068). All patients who received systemic chemotherapy for their primary SBA (n = 74) underwent 5-FU–based regimens.

As MMR-D status is used in chemotherapy decision-making in stage II colorectal cancer (8–11), we assessed chemotherapy utilization and recurrence in stage II SBA alone. While 81.3% (13/16) of stage II patients in the MMR-P group received systemic chemotherapy compared with 50% (4/8) in the MMR-D group, 84.6% (11/13) recurred, compared with 50% (2/4) in the MMR-D group; however, this did not reach statistical significance, likely due to sample size (P = 0.15). Clinical characteristics, treatment, and recurrence rates of all patients with stage II SBA are demonstrated in Supplementary Table S1.

We also assessed utilization and response to immune checkpoint blockade in MMR-D patients. Among the 5 patients with metastatic MMR-D SBAs receiving immunotherapy, 60% (3/5) demonstrated treatment response. One patient with a Lynch syndrome–associated MMR-D SBA was started on immunotherapy after progression of disease (POD) with FOLFIRINOX. While the patient demonstrated no clinical evidence of disease (NED) for 28 months, the patient developed a new primary metastatic MMR-D gastric cancer, which was the ultimate cause of death 6 months later. One additional patient with stage III SBA was placed on FOLFOX and demonstrated POD with development of a metachronous stage IV rectal cancer while on treatment. Immunotherapy was initiated, and that patient is NED for both malignancies. One deceased MMR-D patient only received immunotherapy right before death, as the drug had just received FDA approval.

Etiology of MMR-D

We assessed potential somatic causes of MMR-D among patients with Lynch syndrome–negative SBA (n = 16). While 2 patients declined additional work-up, among remaining patients (n = 14), we identified a somatic driver of MMR-D status in 64.3% (9/14), with the majority of tumors (77.8%; 7/9) demonstrating MLH1 promoter hypermethylation, a known somatic driver of MMR-D (ref. 33; Table 2).

Table 2.

MSI/IHC concordance, germline status, and somatic drivers in MMR-D tumors.

Age at DXMSIsensor scoreIHC resultTumor locationLS-positive (Y/N)SBA was index cancer? (Y/N)SBA detected on surveillance? (Y/N)Personal or family history of SBA? (Y/N)Gene(s) mutated in germlineSomatic driver of MMR-D status
67 NA PMS2 absent Jejunum UNK UNK 
75 53.85 MLH1/PMS2/MSH3 absent Jejunum NR MLH1 hypermethylation 
56 48.09 MLH1/PMS2 absent Duodenum NR MLH1 hypermethylation 
65 43.42 MLH1/PMS2 absent Duodenum NR MLH1 hypermethylation 
70 43.28 MSH2/MSH6 absent Jejunum NEG Hypermutated tumor, POLE exon32 pR1364Vfs*5 
70 40.06 MLH1/PMS2 absent Duodenum NEG Ultramutated tumor. Six somatic POLE mutations, encompassing exonuclease domain. Biallelic somatic MLH1 mutations 
61 36.55 MLH1/PMS2 absent Jejunum NEG MLH1 hypermethylation 
29 35.5 MLH1/PMS2 absent Jejunum Yb APC MLH1 hypermethylation 
71 34.9 NORMAL Jejunum APC I1307K MLH1 hypermethylation 
41 27.02 MLH1/PMS2 absent Jejunum LS NEG UNK 
28 24.19 MLH1/PMS2 absent Jejunum NF1 MLH1 hypermethylation 
82 22.19 MLH1/PMS2 absent Jejunum NEG UNK 
66 20.59 NA Duodenum NEG UNK 
54 18.2 MLH1/PMS2 absenta Duodenum UNK UNK 
65 10.02 NORMAL Duodenum NEG UNK 
57 8.14 MSH2/MSH6 absenta Duodenum NEG UNK 
72 NA MSH2/MSH6 absent Jejunum MSH2; NTHL1 NR 
62 NA MSH2/MSH6 absent Jejunum MSH2 NR 
62 NA MLH1/PMS2 absent Duodenum Yc MLH1 NR 
54 NA MLH1/PMS2 absent Duodenum MLH1 NR 
45 47.28 NA Jejunum MSH2 NR 
44 31.68 MLH1/PMS2 absent Duodenum Yb MLH1 NR 
50 31.29 MLH1 focal/PMS2 absent Duodenum PMS2 NR 
35 25.65 MLH1/PMS2 absent Duodenum MLH1 NR 
44 25.06 NORMAL Ileum MLH1 NR 
44 23.44 PMS2 absent Ileum PMS2 NR 
Age at DXMSIsensor scoreIHC resultTumor locationLS-positive (Y/N)SBA was index cancer? (Y/N)SBA detected on surveillance? (Y/N)Personal or family history of SBA? (Y/N)Gene(s) mutated in germlineSomatic driver of MMR-D status
67 NA PMS2 absent Jejunum UNK UNK 
75 53.85 MLH1/PMS2/MSH3 absent Jejunum NR MLH1 hypermethylation 
56 48.09 MLH1/PMS2 absent Duodenum NR MLH1 hypermethylation 
65 43.42 MLH1/PMS2 absent Duodenum NR MLH1 hypermethylation 
70 43.28 MSH2/MSH6 absent Jejunum NEG Hypermutated tumor, POLE exon32 pR1364Vfs*5 
70 40.06 MLH1/PMS2 absent Duodenum NEG Ultramutated tumor. Six somatic POLE mutations, encompassing exonuclease domain. Biallelic somatic MLH1 mutations 
61 36.55 MLH1/PMS2 absent Jejunum NEG MLH1 hypermethylation 
29 35.5 MLH1/PMS2 absent Jejunum Yb APC MLH1 hypermethylation 
71 34.9 NORMAL Jejunum APC I1307K MLH1 hypermethylation 
41 27.02 MLH1/PMS2 absent Jejunum LS NEG UNK 
28 24.19 MLH1/PMS2 absent Jejunum NF1 MLH1 hypermethylation 
82 22.19 MLH1/PMS2 absent Jejunum NEG UNK 
66 20.59 NA Duodenum NEG UNK 
54 18.2 MLH1/PMS2 absenta Duodenum UNK UNK 
65 10.02 NORMAL Duodenum NEG UNK 
57 8.14 MSH2/MSH6 absenta Duodenum NEG UNK 
72 NA MSH2/MSH6 absent Jejunum MSH2; NTHL1 NR 
62 NA MSH2/MSH6 absent Jejunum MSH2 NR 
62 NA MLH1/PMS2 absent Duodenum Yc MLH1 NR 
54 NA MLH1/PMS2 absent Duodenum MLH1 NR 
45 47.28 NA Jejunum MSH2 NR 
44 31.68 MLH1/PMS2 absent Duodenum Yb MLH1 NR 
50 31.29 MLH1 focal/PMS2 absent Duodenum PMS2 NR 
35 25.65 MLH1/PMS2 absent Duodenum MLH1 NR 
44 25.06 NORMAL Ileum MLH1 NR 
44 23.44 PMS2 absent Ileum PMS2 NR 

Note: Hypermutated tumor defined as >50 somatic mutations. Ultramutated tumor defined as >150 somatic mutations. MSIsensor scores: MSI-H ≥10, MSI-I 3–10, MSS <3. POLE exonuclease domain spanning exons 9–14.

Abbreviations: DX, diagnosis; LS NEG, Lynch syndrome testing negative; LS, Lynch syndrome; NA, not available; NR, not relevant; UNK, unknown, patient lost to follow-up.

aPatient declined additional work-up.

bSynchronous colon cancer.

cFound on screening endoscopic ultrasound completed at outside institution for family history of pancreas cancer.

Among the entire cohort, 76 patients underwent comprehensive tumor/normal paired NGS analysis (MSK-IMPACT). In those undergoing germline genetic assessment (n = 38), in addition to MMR genes, pathogenic and/or likely pathogenic variants were identified in NF1, APC, ATM, BRCA2, MUTYH, and NTHL1, with most (55.6%; 5/9) of these among patients with MMR-P tumors (Supplementary Table S2). Of the 4 patients with non-Lynch syndrome germline mutations but MMR-D tumors, two harbored APC mutations, with one being diagnostic of familial adenomatous polyposis (FAP) and the other being the APC p.I1307K Ashkenazi Jewish founder mutation not implicated in FAP (18, 34, 35). Both patients' tumors demonstrated MLH1 promoter hypermethylation. An additional patient had a known neurofibromatosis type 1 (NF1) diagnosis with an MLH1/PMS2 absent jejunal tumor. The patient received full MSK-IMPACT germline assessment and clinical Lynch syndrome testing, which did not reveal any additional germline findings. A second NF1 somatic mutation was found in the tumor in addition to MLH1 promoter hypermethylation (Supplementary Table S2).

Of note, there was 1 patient with Lynch syndrome with an MSI-H SBA (MSIsensor score 25.06) that had intact MMR protein expression on IHC (Table 2; Supplementary Table S2). The patient had a personal history of endometrial cancer, harbored a germline MLH1 pathogenic missense variant [c.55A>T(p.Ile19Phe)], and had a family history of Lynch syndrome–associated cancers in her mother and maternal grandmother (colorectal cancer and endometrial cancer). Her prior endometrial cancer also demonstrated retained MMR protein expression, suggesting a failed screening test for Lynch syndrome using IHC rather than MSI in this patient in both of her Lynch syndrome–associated malignancies. We have previously reported that germline MMR missense mutations may lead to retained protein expression in the tumor despite demonstrating MSI status (36).

In contrast to colorectal cancer, where the role of MMR-D in Lynch syndrome screening and as a prognostic and predictive marker for clinical outcome has been well established, the role of MMR-D in SBA has not been well characterized, in part, because of the rarity of this malignancy. Our data build upon prior studies demonstrating that the prevalence of MMR-D in SBA may in fact be higher than in colorectal cancer (5, 6), as we identified a slightly increased MMR-D prevalence among SBAs of 26% compared with the reported 15%–20% of colorectal cancer (16, 37, 38). While one prior study characterizing the genomic landscape of SBA reported the MSI-H prevalence in SBA to be 7.6% (6), it is worth noting that only 50% of included tumors were assessed for MSI/MMR-D status, including colorectal cancer, in which only 4% were found to be MSI-H. Perhaps more importantly, as noted by Schrock and colleagues, their cohort was enriched for metastatic cases leading to an underrepresentation of MMR-D tumors, which are more likely to be associated with early-stage disease (5, 6). Interestingly, despite this, they demonstrated a nearly 2-fold increase in MMR-D prevalence in SBA compared with colorectal cancer (7.6% vs. 4%, respectively). Comparatively, our increase in MMR-D prevalence in SBA compared with colorectal cancer was more modest (26% vs. 19%, respectively), but it also aligns with a prior study demonstrating a 23% MMR-D prevalence among a cohort of 61 patients with SBA (5), providing additional supporting evidence that MMR-D prevalence in SBA may be higher than in colorectal cancer.

Second, as in colorectal cancer, our data suggest that MMR-D status appears to predict for earlier stage disease. This observation does not reflect potential screening bias in Lynch syndrome–associated cases, as only 1 patient with Lynch syndrome was found to have SBA during a screening procedure for family history of pancreas cancer (Table 2). Fifty percent of Lynch syndrome–associated SBAs were the patient's index cancer and 80% of our Lynch syndrome cohort had no family history of SBA. In addition, it is not currently recommended for all patients with Lynch syndrome to undergo surveillance for SBA given the lack of proven efficacious methods (39).

Our data also demonstrate that MMR-D SBA may in fact be associated with better disease prognosis, as we found a statistically significantly lower rate of disease recurrence, as only 8% (2/11) of our stage I/II MMR-D cancers recurred compared with 88% (15/17) of stage I/II MMR-P tumors (P = 0.0002). This is analogous to colorectal cancer data, wherein especially in early-stage (II) patients, MMR-D is associated with a significantly better prognosis (10, 11, 32). In fact, on the basis of this improved prognosis and a demonstrated lack of benefit from 5FU–based chemotherapy, NCCN guidelines recommend against the use of adjuvant chemotherapy in patients with stage II MMR-D colorectal cancer, irrespective of other risk features (13). Given that stage-for-stage SBA has worse clinical outcomes than colorectal cancer (2–4), this observation has important implications for identifying low-risk, early-stage patients, namely MMR-D stage II SBA, who could potentially be spared of chemotherapy toxicity. Notably, improved outcomes persisted despite an increased rate of synchronous and/or metachronous cancers among our MMR-D cohort, as more than one-third of patients with MMR-D SBA had synchronous and/or metachronous cancers compared with less than 10% in the MMR-P group. Not surprisingly, the majority (66.7%) were in patients with Lynch syndrome. Given our small sample size in this rare malignancy, additional large-scale studies are needed to best inform treatment decisions specific to stage II SBA.

We identified a 10% (10/100) Lynch syndrome prevalence in SBA overall, and a 38.5% (10/26) prevalence among MMR-D tumors. Moreover, we identified a 2-fold increase in Lynch syndrome prevalence among MMR-D SBAs compared with that of our MMR-D colorectal cancer cases (38.5% vs. 19%, respectively; ref. 16).

Despite the relatively small sample size of Lynch syndrome–associated SBA, we noted a consistent trend among the distribution of germline mutations when comparing with Lynch syndrome–associated colorectal cancer, as 80% (8/10) of patients with Lynch syndrome–associated SBAs had underlying MLH1 and MSH2 germline mutations. This is not surprising, as mutations in MLH1 and MSH2 are considered to be highly penetrant (16, 40, 41). We also noted that 20% (2/10) of patients with Lynch syndrome–associated SBAs harbored PMS2 germline mutations. Both were found to have concordant IHC and MSIsensor scores (Table 2), suggesting the PMS2 germline mutation was driving the malignancy. This is important to highlight as the penetrance of PMS2 mutations is an ongoing area of controversy, in which some groups argue for revised clinical management, suggesting that PMS2 mutation carriers are not at a significantly increased risk of extracolonic malignancies above the general population (42–44). In addition, while we did find additional germline mutations in other cancer predisposition genes, as we did not perform uniform multi-gene panel testing across the entire cohort, the implications of such findings are beyond the scope of this study. Additional research is warranted.

There are several limitations to our study. First, this was a retrospective study across a single institution; however, the uniformity of clinical and genomic characterization allowed for in-depth analysis. Second, our cohort reflects that of a large referral center, primarily comprised of non-Hispanic White patients. Third, as our cases of Lynch syndrome–associated SBA were diagnosed at a significantly younger age than in MMR-D non-Lynch syndrome SBA (47.5 vs. 65, respectively), and prior research in rectal cancer has demonstrated that younger age may predict for higher LN yield and positivity (45), it is possible that age may be a confounder of LN yield in our Lynch syndrome population. However, because clinical outcomes were compared between MMR-P versus all other MMR-D SBAs, inclusive of patients with Lynch syndrome, this difference in our small Lynch syndrome cohort did not drive the improved outcomes demonstrated. Finally, our study population size was relatively small, again reflecting the rarity of this malignancy. However, to our knowledge, this is the largest study comparing clinical outcomes and systemic treatment response of patients with SBA according to MMR and germline status.

Our analysis demonstrates that among SBAs, there is a significant proportion of underlying MMR-D tumors, as we found that more than one-fourth of our SBA cohort was MMR-D. Given the recently updated NCCN guidelines recommending MMR-D assessment in SBA, we would suspect the true MMR-D proportion will soon be elucidated as clinicians become accustomed to incorporating this into routine management as is done in colorectal cancer (7). Moreover, 50% of patients with Lynch syndrome presented with SBA as their index cancer and would not have been identified as having Lynch syndrome had they not undergone MMR assessment. As it is standard of care for all colorectal cancers to have MMR-D assessment and subsequent Lynch syndrome testing in MMR-D colorectal cancers, there is low likelihood of an underestimation of Lynch syndrome among colorectal cancers. Taken together, this seemingly suggests that MMR-D status among SBAs may be more predictive of underlying Lynch syndrome than in colorectal cancers. As such and given the implications for patients and their at-risk relatives, MMR-D assessment in all SBAs with subsequent germline testing for Lynch syndrome is warranted.

D.L. Reidy-Lagunes reports grants from Merck, Ipsen, grants and other from Novartis, and other from Lexicon and Chiasma outside the submitted work. N.H. Segal reports personal fees from Boehringer Ingelheim, Roche/Genentech, ABL Bio, Revitope, PsiOxus, Immunocore, PureTech Ventures, Amgen, and GlaxoSmithKline and grants from Merck, BMS, AstraZeneca, Incyte, Immunocore, Roche/Genentech, and Pfizer outside the submitted work. R. Yaeger reports personal fees from Natera, grants and personal fees from Array BioPharma/Pfizer, and grants from Boehringer Ingelheim outside the submitted work. G.M. Nash reports nonfinancial support from Intuitive Surgical outside the submitted work. A. Zehir reports personal fees from Illumina outside the submitted work. M.F. Berger reports personal fees from Roche and grants from Grail outside the submitted work. A. Cercek reports personal fees from Bayer, Array and Biopharma and grants from Tesaro/GlaxoSmithKline, Seattle Genetics, and RGenix outside the submitted work. J. Garcia-Aguilar reports other from Ethicon J&J, Intuitive Surgical, and Medtronics outside the submitted work. Z.K. Stadler reports other from Genentech/Roche, Novartis, RegenexBio, Neurogene, Optos Plc, Regeneron, Allergan, Gyroscope Tx, and Adverum outside the submitted work. No disclosures were reported by the other authors.

A. Latham: Conceptualization, data curation, formal analysis, investigation, visualization, writing-original draft, writing-review and editing. J. Shia: Resources, data curation, methodology, writing-review and editing. Z. Patel: Data curation, project administration. D.L. Reidy-Lagunes: Resources, data curation, writing-review and editing. N.H. Segal: Resources, data curation, writing-review and editing. R. Yaeger: Resources, data curation, writing-review and editing. K. Ganesh: Resources, data curation, writing-review and editing. L. Connell: Resources, data curation, writing-review and editing. N.E. Kemeny: Resources, data curation, writing-review and editing. D.P. Kelsen: Resources, data curation, writing-review and editing. J.F. Hechtman: Resources, data curation, writing-review and editing. G.M. Nash: Resources, data curation, writing-review and editing. P.B. Paty: Resources, data curation, writing-review and editing. A. Zehir: Resources, methodology, writing-review and editing. K.A. Tkachuk: Data curation, writing-review and editing. R. Sheikh: Resources, data curation, writing-review and editing. A.J. Markowitz: Resources, data curation, writing-review and editing. D. Mandelker: Resources, data curation, methodology, writing-review and editing. K. Offit: Resources, data curation, writing-review and editing. M.F. Berger: Resources, methodology, writing-review and editing. A. Cercek: Resources, data curation, writing-review and editing. J. Garcia-Aguilar: Resources, data curation, writing-review and editing. L.B. Saltz: Resources, data curation, writing-review and editing. M.R. Weiser: Resources, data curation, writing-review and editing. Z.K. Stadler: Conceptualization, resources, data curation, formal analysis, funding acquisition, methodology, writing-original draft, writing-review and editing.

This research was funded, in part, through the Romeo Milio Lynch Syndrome Foundation, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, the Robert and Kate Niehaus Center for Inherited Cancer Genomics, the Fieldstone Family Fund, and the NIH/NCI Cancer Center Support grant P30 CA008748.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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