Abstract
Background
Pathogenic variants of the DPYD gene are strongly associated with grade ≥3 toxicity during fluoropyrimidine chemotherapy. We conducted a systematic review and meta‐analysis to estimate the risk of treatment‐related death associated with DPYD gene variants.
Materials and Methods
We searched for reports published prior to September 17, 2020, that described patients receiving standard‐dose fluoropyrimidine chemotherapy (5‐fluorouracil or capecitabine) who had baseline testing for at least one of four pathogenic DPYD variants (c.1129‐5923C>G [HapB3], c.1679T>G [*13], c.1905+1G>A [*2A], and c.2846A>T) and were assessed for toxicity. Two reviewers assessed studies for inclusion and extracted study‐level data. The primary outcome was the relative risk of treatment‐related mortality for DPYD variant carriers versus noncarriers; we performed data synthesis using a Mantel‐Haenszel fixed effects model.
Results
Of the 2,923 references screened, 35 studies involving 13,929 patients were included. DPYD variants (heterozygous or homozygous) were identified in 566 patients (4.1%). There were 14 treatment‐related deaths in 13,363 patients without identified DPYD variants (treatment‐related mortality, 0.1%; 95% confidence interval [CI], 0.1–0.2) and 13 treatment‐related deaths in 566 patients with any of the four DPYD variants (treatment‐related mortality, 2.3%; 95% CI, 1.3%–3.9%). Carriers of pathogenic DPYD gene variants had a 25.6 times increased risk of treatment‐related death (95% CI, 12.1–53.9; p < .001). After excluding carriers of the more common but less deleterious c.1129‐5923C>G variant, carriers of c.1679T>G, c.1905+1G>A, and/or c.2846A>T had treatment‐related mortality of 3.7%.
Conclusion
Patients with pathogenic DPYD gene variants who receive standard‐dose fluoropyrimidine chemotherapy have greatly increased risk for treatment‐related death.
Implications for Practice
The syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency is an uncommon but well‐described cause of severe toxicity related to fluoropyrimidine chemotherapy agents (5‐fluorouracil and capecitabine). Patients with latent DPD deficiency can be identified preemptively with genotyping of the DPYD gene, or with measurement of the plasma uracil concentration. In this systematic review and meta‐analysis, the authors study the rare outcome of treatment‐related death after fluoropyrimidine chemotherapy. DPYD gene variants associated with DPD deficiency were linked to a 25.6 times increased risk of fluoropyrimidine‐related mortality. These findings support the clinical utility of DPYD genotyping as a screening test for DPD deficiency.
Keywords: 5‐fluorouracil, Capecitabine, DPYD, Dihydropyrimidine dehydrogenase deficiency, Pharmacogenomics
Short abstract
This systematic review of the literature analyzes the risk of fluoropyrimidine chemotherapy treatment‐related death associated with DPYD gene variants.
Introduction
Fluoropyrimidine chemotherapy drugs, including 5‐fluorouracil and its oral prodrug capecitabine, play an essential role in the treatment of gastrointestinal, breast, and head and neck cancers. Toxicities of fluoropyrimidine chemotherapies are well‐described, and include neutropenia, mucositis, diarrhea, and hand‐foot syndrome. Although changes in the administration and dosing of fluoropyrimidines have led to reductions in treatment‐related toxicity in recent decades, approximately 15%–20% of patients receiving fluoropyrimidine monotherapy will have severe drug‐related adverse effects (grade 3 or higher) during the course of treatment [1, 2]. Grade ≥3 toxicities are still more common among patients receiving fluoropyrimidine‐based combination chemotherapy, affecting up to 56% of patients [3]. Treatment‐related deaths (grade 5 toxic events) are rare during fluoropyrimidine‐based chemotherapy, occurring in less than 1% of patients [3, 4, 5]. However, uncommon variants of the DPYD gene are increasingly recognized as a significant cause of severe and sometimes fatal fluoropyrimidine toxicity [6, 7].
The DPYD gene encodes dihydropyrimidine dehydrogenase (DPD), the rate‐limiting enzyme in fluoropyrimidine metabolism, and deficiency of DPD enzymatic function leads to toxic accumulation of fluoropyrimidine metabolites [6, 8]. Germline variants in DPYD are the predominant cause of DPD deficiency, and pathogenic DPYD variants have been linked to a 5–8 times increased odds of grade 3 or higher toxicity [9, 10]. At least four DPYD alleles are widely recognized for their association with severe toxicity, including c.1129‐5923 C>G (HapB3), c.1679T>G (*13), c.1905+1G>A (*2A), and c.2846A>T [11]. The combined carrier frequency of these four alleles in European and North American populations is approximately 2%–8% [12, 13].
Although there has been extensive investigation into the risk of moderate‐to‐severe fluoropyrimidine toxicity in patients with pathogenic DPYD variants, reliable estimates for the risk of treatment‐related death in these patients are lacking, primarily because of the rarity of grade 5 events in unselected patients. We conducted a systematic review and meta‐analysis to better estimate the risk of treatment‐related death in carriers of pathogenic DPYD gene variants who receive standard‐dose fluoropyrimidine chemotherapy.
Materials and Methods
Systematic Review
We conducted a systematic literature review, with adherence to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement [14]. The study protocol was reviewed by the Committee for the Protection of Human Subjects at Dartmouth College, with a determination that the research did not meet the regulatory definition of human subject research. This review is registered in the PROSPERO prospective register of systematic reviews (ID CRD42020144921) [15, 16].
We initially searched the MEDLINE (PubMed), Embase (OVID), Web of Science, and Cochrane Library (Wiley) databases to identify relevant articles published prior to January 24, 2018; the search was limited to English language reports (papers and abstracts). We subsequently updated and repeated our search to include reports published through September 17, 2020. The final search strategy employed a combination of Medical Subject Heading terms and keyword terms. The search strategy was adjusted for the syntax appropriate to each database. A description of the terms used in the MEDLINE search is included in Table 1; similar terms were used in the Embase, Web of Science, and Cochrane Library searches.
Table 1.
MEDLINE search strategy
| Search | Query | Results |
|---|---|---|
| #1 | Search: “Dihydropyrimidine Dehydrogenase Deficiency”[MeSH] OR “Dihydrouracil Dehydrogenase (NADP)”[MeSH] OR Dihydrouracil dehydrogenase[tiab] OR Dihydropyrimidine dehydrogenase[tiab] OR DPYD*[tiab] OR DPD[tiab] OR 1905+1G>A[tiab] OR c.1905+1G>A[tiab] OR IVS14+1G>A[tiab] OR rs3918290[tiab] OR 2846A>T[tiab] OR c.2846A>T[tiab] OR D949V[tiab] OR p.D949V[tiab] OR Asp949Val[tiab] OR p.Asp949Val[tiab] OR rs67376798[tiab] OR 1679T>G[tiab] OR c.1679T>G[tiab] OR I560S[tiab] OR p.I560S[tiab] OR Ile560Ser[tiab] OR p.Ile560Ser[tiab] OR rs55886062[tiab] OR HapB3[tiab] OR 1129‐5923C>G[tiab] OR c.1129‐5923C>G[tiab] OR 1236G>A[tiab] OR c.1236G>A[tiab] OR E412E[tiab] OR p.E412E[tiab] OR Glu412Glu[tiab] OR p.Glu412Glu[tiab] OR rs56038477[tiab] OR rs75017182[tiab] | 4,222 |
| #2 | Search: “Fluorouracil”[MeSH] OR “Capecitabine”[MeSH] OR 5Fluorouracil[tiab] OR 5‐Fluorouracil[tiab] OR Fluorouracil[tiab] OR 5FU[tiab] OR 5‐FU[tiab] OR Capecitabine[tiab] OR Fluoropyrimidine*[tiab] | 64,546 |
| #3 | Search: “Humans”[MeSH] OR patient*[tiab] OR human*[tiab] | 20,251,398 |
| #4 | Search: #1 AND #2 AND #3 | 1,550 |
We limited our review to research publications and abstracts describing studies of adult patients with solid tumor (nonhematologic) malignancies treated with standard doses of fluoropyrimidine chemotherapy (5‐fluorouracil or capecitabine). We further limited our review to studies in which patients were systematically tested for one or more of the four pathogenic DPYD variants of interest (c.1129‐5923C>G, c.1679T>G, c.1905+1G>A, and/or c.2846A>T) with prospective biospecimen collection and followed after chemotherapy initiation for assessment of treatment‐related adverse events. We excluded case‐control studies and other studies that selectively tested patients for DPYD gene variants based on toxicities or decreased DPD activity, as well as studies that did not identify carriers of any of the four variants of interest.
We conducted the manual review of studies in two phases. In the initial phase we screened study titles and abstracts to identify potentially eligible studies, using the Rayyan software app to organize the review process (Cambridge, Massachusetts,U.S.A.) [17]. In the second phase we reviewed the full text of published manuscripts and abstracts to determine study inclusion and exclusion, referencing published appendix materials as necessary. In cases in which overlapping cohorts were described in multiple reports, we abstracted a single record for the cohort using relevant data from any of the published reports. Each stage of the review process was carried out in duplicate by two independent reviewers, and conflicting decisions were resolved through discussion among authors B.B.S., K.R., and G.A.B.
Data Extraction
Two reviewers extracted relevant data from published manuscripts, appendix materials, and abstracts of included studies. Data items collected included study design, study location, characteristics of the patient population, fluoropyrimidine agent (5‐fluoroacil [5‐FU], capecitabine, or either), chemotherapy regimen type (fluoropyrimidine monotherapy or combination chemotherapy), treatment setting (adjuvant, metastatic, or unspecified), DPYD variants evaluated, the number of patients evaluated for each DPYD variant, the number of patients with identified DPYD variants, the number of patients with treatment‐related mortality (i.e., grade 5 toxicity), and any available information about the DPYD genotype of decedents. We accepted author reporting of treatment‐related deaths, as opposed to cancer‐related mortality, based on study‐specific definitions or reporting. We contacted study authors by e‐mail with requests for clarification when information regarding the number of variant carriers, the number of decedents, or the genotype of decedents was unclear. Data were collected and managed using study‐specific REDCap electronic data capture tools (Vanderbilt University, Nashville, TN) hosted at the Dartmouth‐Hitchcock Medical Center [18, 19].
Risk‐of‐Bias Evaluation
We used the CLARITY Tool to assess risk of bias in cohort studies to guide our risk‐of‐bias evaluation [20]. The study design controlled for items 1–5, 7, and 8 in the CLARITY Tool. We evaluated the risk of bias in our analysis by answering question 6 of the tool, which reads “Can we be confident in the assessment of [the] outcome?” (Categorized as “yes,” “probably yes,” “probably no,” or “no”). Studies were classified as “yes” if explicit mention was made that treatment‐related deaths (or grade 5 toxicities) did or did not occur. Studies were classified as “probably yes” if there was detailed reporting of adverse events and grading of events, without explicit mention that treatment‐related deaths did or did not occur. Studies that reported only summary information about adverse events were classified as “probably no.” When assessing for risk of bias in reporting of treatment‐related mortality, we used all available information collected for each study, including author query e‐mail responses, when available.
Data Synthesis
The primary study outcome was the relative risk of treatment‐related mortality in patients who were carriers of pathogenic DPYD variants, compared with noncarriers. Treatment‐related mortality is a rare event (with no observed events from one or both cohorts of many of the included studies), and meta‐analysis of rare events poses special methodological challenges [21, 22]. We pooled the study‐level data using a Mantel‐Haenszel fixed effects model. An advantage of this approach is that it does not employ an arbitrary continuity correction for studies with no events in one of two compared groups [21]; however, studies with no events in either of the two compared groups are excluded from the pooled analysis of relative risk with this approach. Study heterogeneity was assessed using the I2 index [23].
We performed two sensitivity analyses for the comparison of patients with and without identified DPYD variants. The first sensitivity analysis excluded studies with high risk of bias, in which confidence in the outcome assessment was lacking. The second sensitivity analysis excluded studies of fewer than 200 patients, in which publication bias could lead to selective publication of studies with higher incidence of treatment‐related adverse events.
We also estimated the absolute risk of treatment‐related mortality for subgroups of patients defined by their carrier status for specific DPYD variants. Subgroups included patients with of any of the four DPYD variants evaluated, each of the four studied DPYD variants individually, and for the group of patients with any one of the three variants including c.1679T>G, c.1905+1G>A, and/or c.2846A>T (excluding patients with only the c.1129‐5923C>G genotype, which may confer lesser risk for severe toxicity than the other three variants [24]). We used Mantel‐Haenszel fixed effects models to construct pooled estimates of absolute mortality risk across the included studies (including studies with no treatment‐related deaths.)
Statistical analyses were implemented in R (R Foundation, Vienna), using package “meta” [25, 26]. Lastly, we composed a narrative synthesis to describe treatment‐related mortality among patients with homozygosity or compound heterozygosity for pathogenic DPYD variants.
Results
Search Results
Our database search identified 2,928 unique study records. After dual review of manuscripts and abstracts captured in the initial search, we identified 35 studies for inclusion in our analysis [10, 13, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59]. Details of the review process are shown in Figure 1. Ten of 35 included studies were prospective clinical trials, 16 were prospective cohort studies, and 9 were retrospective studies of cohorts with prospective biospecimen collection. Aggregate characteristics of included studies are shown in Table 2 and individual studies are described in Table 3.
Figure 1.
PRISMA diagram of included studies.
Table 2.
Summary characteristics of 35 included studies and 13,929 included patients
| Characteristics | Studies, n (%) | Patients tested for ≥1 DPYD variant, n (%) |
|---|---|---|
| Study design | ||
| Clinical trial | 10 (28.6) | 8,422 (60.5) |
| Observational study, prospective | 16 (45.7) | 2,813 (20.2) |
| Observational study, retrospective | 9 (25.7) | 2,694 (19.3) |
| Number of patients in cohort | ||
| <200 | 16 (45.7) | 1,404 (10.1) |
| ≥200 | 19 (54.3) | 12,525 (89.9) |
| Study continent | ||
| Europe | 26 (74.3) | 9,925 (71.3) |
| Asia | 6 (17.1) | 525 (3.8) |
| North America | 3 (8.6) | 3,479 (25.0) |
| Cancer site | ||
| Colorectal | 20 (57.1) | 9,603 (68.9) |
| Gastrointestinal (noncolorectal) | 2 (5.7) | 127 (0.9) |
| Breast | 2 (5.7) | 348 (2.5) |
| Multiple sites included | 11 (31.4) | 3,851 (27.6) |
| Treatment setting | ||
| Adjuvant | 5 (14.3) | 5,625 (40.4) |
| Metastatic | 11 (31.4) | 2,877 (20.7) |
| Mixed or not described | 19 (54.3) | 5,427 (39.0) |
| Fluoropyrimidine agent | ||
| 5‐FU | 15 (42.9) | 8,405 (60.3) |
| Capecitabine | 7 (20.0) | 2,083 (15.0) |
| 5‐FU or capecitabine | 13 (37.1) | 3,441 (24.7) |
| Chemotherapy regimen type | ||
| Monotherapy only | 4 (11.4) | 1,782 (12.8) |
| Combination therapy a | 31 (88.6) | 12,147 (87.2) |
| DPYD gene variants assessed | ||
| c.1129‐5923C>G | 11 (31.4) | 6,242 (44.8) |
| c.1679T>G | 17 (48.6) | 8,799 (63.2) |
| c.1905+1G>A | 35 (100) | 13,929 (100) |
| c.2846A>T | 23 (65.7) | 10,759 (77.2) |
Multi‐arm studies were classified as combination therapy if any of the study arms involved combination chemotherapy.
Abbreviation: 5‐FU, 5‐fluorouracil.
Table 3.
Descriptive characteristics of 35 studies included in the systematic review
| Study | Study design | DPYD genotypes evaluated | DPYD variant carriers, n / Patients evaluated, n a | Deaths in variant carriers, n / All deaths, n | Confident in outcome assessment [20]? |
|---|---|---|---|---|---|
| Salgueiro, 2004 [27] | PC | c.1905+1G>A | 1/73 | 0 | Yes |
| Largillier, 2006 [28] | PC | c.1905+1G>A | 1/105 | 1/1 | Probably yes |
| Morel, 2006 [29] | PC | c.1679T>G, c.1905+1G>A, c.2846A>T | 21/487 | 1/1 | Yes |
| Salgado, 2007 [30] | PC | c.1905+1G>A | 1/58 | 0 | Yes |
| Schwab, 2008 [31] | CT | c.1905+1G>A | 13/683 | 0 | Yes |
| Gross, 2008 [32] | RC | c.1129‐5923C>G, c.1905+1G>A, c.2846A>T | 7/128 | 0/2 | Yes |
| Braun, 2009 (FOCUS) [33] | CT | c.1905+1G>A | 4/629 | 0 | Probably no b |
| Boige, 2010 (FFCD 2000‐005) [34] | CT | c.1905+1G>A | 2/346 | 0 | Probably yes b |
| Ceric, 2010 [35] | PC | c.1905+1G>A | 1/50 | 1/2 | Yes |
| Kristensen, 2010 [36] | RC | 1679T>G, c.1905+1G>A, c.2846A>T | 3/68 | 0 | Yes |
| Deenen, 2011 (CAIRO2) [37] | CT | c.1129‐5923C>G, 1679T>G, c.1905+1G>A, c.2846A> | 44/568 | 1/1 | Probably yes |
| Dhawan, 2013 [38] | PC | c.1905+1G>A, c.2846A>T | 9/23 | 0 | Probably no |
| Loganayagam, 2013 [39] | RC | c.1129‐5923C>G, 1679T>G, c.1905+1G>A, c.2846A>T | 25/430 | 0 | Yes |
| Jennings, 2013 [40] | PC | c.1129‐5923C>G, c.1905+1G>A, c.2846A>T | 15/254 | 1/4 | Yes |
| Rosmarin, 2014 (QUASAR2) [10] | CT | c.1905+1G>A, c.2846A>T c | 54/909 | 2/2 | Yes |
| Cai, 2014 [41] | PC | c.1905+1G>A | 13/80 | 0 | Probably no |
| Froehlich, 2015 [42] | PC | c.1129‐5923C>G, 1679T>G, c.1905+1G>A, c.2846A>T | 32/500 | 1/1 | Probably yes |
| Lee, 2014 (NCCTG N0147) [13, 24] | CT | c.1129‐5923C>G, 1679T>G, c.1905+1G>A, c.2846A>T | 133/2,594 | 1/1 | Probably yes |
| Etienne‐Grimaldi, 2014 [43] | CT | c.1905+1G>A | 3/205 | 0 | Yes b |
| Joerger, 2015 [44] | PC | c.1905+1G>A, c.2846A>T | 8/140 | 0 | Yes b |
| Falvella, 2015 [45] | PC | c.1129‐5923C>G, 1679T>G, c.1905+1G>A, c.2846A>T | 3/64 | 0 | Probably yes |
| Toffoli, 2015 [46] | RC | 1679T>G, c.1905+1G>A, c.2846A>T | 18/603 | 1/1 | Probably yes |
| Ohnuma, 2015 [47] | RC | c.1905+1G>A | 1/103 | 0 | Probably yes |
| Boige, 2016 (PETACC‐8) [48] | CT | c.1129‐5923C>G, 1679T>G, c.1905+1G>A, c.2846A>T | 89/1,545 | 0 | Yes b |
| Botticelli, 2017 [49] | RC | c.1905+1G>A, | 6/638 | 0 | Yes b |
| Boisdron‐Celle, 2017 [50] | PC | c.1679T>G, c.1905+1G>A, c.2846A>T | 11/398 | 1/1 | Yes |
| Etienne‐Grimaldi, 2017 [51] | PC | c.1129‐5923C>G, 1679T>G, c.1905+1G>A, c.2846A>T | 11/243 | 1/1 | Yes |
| Ruzzo, 2017 (TOSCA) [52] | CT | c.1679T>G, c.1905+1G>A, c.2846A>T | 9/508 | 0 | Yes b |
| Vivaldi, 2017 [53] | PC | c.1679T>G, c.1905+1G>A, c.2846A>T | 1/104 | 0 | Yes b |
| Nahid, 2018 [54] | PC | c.1905+1G>A | 8/161 | 0 | Probably yes |
| Cremolini, 2018 (TRIBE) [55] | CT | c.1679T>G, c.1905+1G>A, c.2846A>T | 10/439 | 1/9 | Yes b |
| Amirfallah, 2018 [56] | RC | c.1679T>G, c.1905+1G>A, c.2846A>T | 1/85 | 0 | Probably no |
| Toffoli, 2019 [57] | RC | c.1129‐5923C>G, 1679T>G, c.1905+1G>A, c.2846A>T | 37/550 | 0 | Yes |
| Alvarado Fernández, 2019 [58] | RC | c.1129‐5923C>G, 1679T>G, c.1905+1G>A, c.2846A>T | 3/89 | 0 | Probably yes |
| Negarandeh, 2020 [59] | PC | c.1905+1G>A, c.2846A>T | 4/73 | 0 | Probably yes |
Numerator indicates number of patients carrying one or more DPYD variants. Denominator indicates the number of patients in the cohort who were tested for one or more DPYD variants.
Response from author query contributed to the assessment of confidence in outcome assessment.
Data from this study for carriers of c.1129‐5923C>G was excluded because of methodologic concerns. Carrier status for c.1129‐5923C>G was imputed using rs281121; this reference single nucleotide polymorphism is located on chromosome 5, whereas the DPYD gene localizes to chromosome 1.
Abbreviations: CT, clinical trial; PC, prospective cohort, RC, retrospective cohort.
Risk‐of‐Bias Assessment
We identified incomplete outcome assessment (incomplete assessment and reporting of treatment‐related death) as the primary risk of bias affecting our analysis. After incorporating information from responses to author queries, we assessed 19 included studies (54%) as having low risk of bias in outcome reporting, 12 studies (34%) as having moderate risk of bias, and 4 studies (11%) as having high risk of bias. Studies at very high risk of bias (very low confidence in outcome assessment) were excluded by the study design.
DPYD Variants and Association with Treatment‐Related Mortality
The study evaluated 13,929 patients for one or more DPYD variant (including c.1129‐5923C>G, c.1679T>G, c.1905+1G>A, and/or c.2846A>T) across the 35 included studies. Pathogenic DPYD variants were identified in 566 patients (4.1%). The pooled carrier frequency for each of the four studied DPYD variants is shown in Table 4. The c.1129‐5923C>G genotype was the most common abnormality, occurring in 3.9% of 6,242 patients evaluated for this variant. Study‐level information about patients tested for individual DPYD variants is shown in the supplemental online Table 1.
Table 4.
Risk of death by DPYD genotype in patients undergoing standard‐dose fluoropyrimidine chemotherapy
| DPYD variants | Patients tested, n | Variant carriers, n (%) | Deaths in variant carriers, n a | Risk of death in variant carriers, % (95% CI) |
|---|---|---|---|---|
| c.1129‐5923C>G | 6,242 | 241 (3.9) | 1 | 0.4 (0.1–2.9) |
| c.1679T>G | 8,799 | 17 (0.2) | 1 | 5.9 (0.8–32.0) |
| c.1905+1G>A | 13,929 | 183 (1.3) | 8 | 4.4 (2.2–8.5) |
| c.2846A>T | 10,759 | 127 (1.2) | 5 | 3.9 (1.7–9.1) |
| Any of four variants (c.1236G>A, c.1679T>G, c.1905+1G>A, or c.2846A>T) | 13,929 b | 566 (4.1) | 13 | 2.3 (1.3–3.9) |
| Any of three variants (c.1679T>G, c.1905+1G>A, or c.2846A>T) | 13,929 b | 325 (2.3) | 12 | 3.7 (2.1–6.4) |
Two deaths occurred in patients with compound heterozygosity of DPYD gene variants.
Includes patients with evaluation for one or more of the four studied variants.
Abbreviations: CI, confidence interval.
Twenty‐seven treatment‐related deaths were reported among 13,929 patients receiving standard doses of fluoropyrimidine‐based chemotherapy, for a crude treatment‐related mortality rate of 0.2%. At least one treatment‐related death was reported in 13 of the 35 studies. There were 14 treatment‐related deaths in 13,364 patients without identified DPYD variants (mortality = 0.1%; 95% CI, 0.1–0.2) and 13 treatment‐related deaths in 566 patients with identified DPYD variants (mortality = 2.3%; 95% CI, 1.3%–3.9%). Estimates of risk for treatment‐related mortality associated with specific DPYD gene variants are shown in Table 4.
The 13 studies with at least one treatment‐related death contributed to the meta‐analytic estimate of relative risk. Patients who were carriers of a pathogenic DPYD gene variant had a 25.6 times increased risk of treatment‐related mortality (95% CI, 12.1–53.9; I2 = 8.2%). The forest plot summarizing the results of individual studies contributing to the pooled estimate results is shown in Figure 2. The findings of the main analysis are supported by two prespecified sensitivity analyses; one limited to the 31 studies with low to moderate risk of bias in outcome assessment (risk ratio [RR] = 21.6; 95% CI, 9.8–47.5) and the second limited to 19 studies of ≥200 patients (RR = 29.3; 95% CI, 12.2–70.2).
Figure 2.
Forest plot for the association of DPYD variants with treatment‐related death. Abbreviations: CI, confidence interval; RR, risk ratio.
Homozygosity and Compound Heterozygosity
Among the 566 patients carrying pathogenic DPYD variants, seven patients had identified homozygosity or compound heterozygosity of pathogenic DPYD variants. Three patients were reported to be homozygous for c.1905+1G>A; no deaths were reported in these patients, although all had grade 4 toxicity [29, 41]. Two patients were reported to be homozygous for c.1129‐5923 C>G, with one experiencing treatment‐related death [13, 42]. Two patients had compound heterozygosity, including one patient who was a carrier of c.1905+1G>A and c.2846A>T and another patient who was a carrier of c.1679G>A and c.1905+1G>A; both patients had treatment‐related death [13, 46].
Discussion
The most commonly reported safety outcome in studies of chemotherapy treatment is the incidence of grade 3 or higher adverse events, as codified by the Common Terminology Criteria for Adverse Events (CTCAE) [60]. Treatment‐attributable deaths are coded as grade 5 toxicities on the CTCAE scale; however, these events are rare enough in most studies (typically occurring in fewer than 1% of patients) that grade 5 toxicities are rarely reported as a key safety outcome. Still, there can be little debate that treatment‐related deaths are the most consequential toxicity events in cancer treatment.
In this systematic review and pooled analysis, we describe the risk of treatment‐related mortality in patients with and without uncommon pathogenic variants of the DPYD gene who received fluoropyrimidine‐containing chemotherapy (5‐FU or capecitabine). Across the 35 included studies we identified 27 deaths in 13,929 patients, for a crude risk of treatment‐related death risk of 0.2%. This observed risk is similar to mortality figures reported in other large cohorts; the IDEA collaborators reported 19 treatment‐related deaths among 12,834 patients receiving adjuvant FOLFOX or CAPOX (mortality risk = 0.15%) [3], and Cheung et al. report a 60‐day mortality risk of 0.6% among 37,568 patients with colon cancer participating in clinical trials of adjuvant therapy between 1977 and 2016 [5].
Although treatment‐related mortality was generally low across the studies included in our analysis, patients with uncommon DPYD variants had an estimated 25.6 times increased risk for treatment‐related death. The absolute risk of death among patients carrying any of the four evaluated DPYD variants was 2.3%. Risk of death was still higher after excluding the more common but less deleterious c.1129‐5923 C>G variant; patients carrying the c.1905+1G>A, c.1679T>G, or c.2846A>T variants had a mortality risk of 3.7%. These findings suggest that the number needed to test to prevent one treatment‐related death with DPYD genotyping is approximately 1,000–1,200 patients, (with a number needed to treat to prevent grade ≥3 toxicity that is considerably lower).
Our findings describe the largest analysis to date of treatment‐related mortality in DPYD variant carriers. Deenen et al. have previously estimated a treatment‐related mortality of roughly 10% in patients carrying the DPYD c.1905+1G>A variant, based on their systematic review of 3,974 patients (with 5 deaths among 48 patients carrying the c.1905+1G>A variant) [7]. It is particularly notable in our analysis that DPYD variants were identified in roughly half of all patients who experienced treatment‐related mortality. It is possible that still more of the decedents carried unidentified DPYD abnormalities, as genotype information was incomplete for one or more of the four variants of interest in each of the decedents without an identified variant of the DPYD gene.
Our analysis adds to a strong and growing evidence base demonstrating that DPYD variants lead to increased risk of severe and sometimes fatal toxicity during treatment with standard‐dose fluoropyrimidine chemotherapy. This evidence base includes at least three prospective studies linking pharmacogenetic testing and proactive chemotherapy dose reduction with lower risk for severe toxicities and deaths [7, 12, 50]. Recommendations for genotype‐guided fluoropyrimidine dose reductions have been formalized in an iteratively‐revised guideline from the Clinical Pharmacogenetics Implementation Consortium [61], and there are growing calls to implement universal DPYD variant testing (or other screening for DPD deficiency) prior to fluoropyrimidine chemotherapy [62, 63]. In April of 2020 the European Medicines Agency took the regulatory stance of recommending universal DPD deficiency screening for European patients prior to fluoropyrimidine chemotherapy [64], and screening for DPD deficiency has become standard practice in many areas of Europe and the U.K.
Screening for pathogenic DPYD gene variants or DPD deficiency is not formally recommended by U.S. authorities at this time. Nevertheless, the U.S. Food and Drug Administration (FDA) has taken multiple actions in recent years in recognition of the risk of severe toxicity from fluoropyrimidine chemotherapy. In December of 2015 the FDA approved uridine triacetate as an antidote to overdose or early‐onset severe toxicity from 5‐fluorouracil or capecitabine, when given within 96 hours of last drug exposure. Approval was based on two studies of 135 patients combined, and 87% of these patients had fluoropyrimidine overdose rather than early‐onset toxicity [65]. The efficacy of uridine triacetate for preventing severe, delayed onset fluoropyrimidine toxicity in carriers of pathogenic DPYD gene variants is unknown, as severe symptoms in carriers of DPYD gene variants often present greater than 96 hours after drug exposure. Additionally, in February of 2020 the FDA published its Table of Pharmacogenetic Associations, therein recognizing that pathogenic DPYD gene variants are associated with increased risk of “severe, life‐threatening or fatal toxicities” from fluorouracil or capecitabine and that data support therapeutic management recommendations for carriers of these variants [66].
A key strength of this study is the systematic approach to identify rare events in unselected patients with and without uncommon genetic variants. Our findings must be interpreted in the context of certain limitations. Although our search strategy excluded studies with the highest risk for bias, we could not eliminate all sources of bias. Only 9 of the 35 included studies assessed each of the four DPYD variants of interest, and it is likely that some decedents without identified DPYD variants may have been misclassified. Because treatment‐related mortality is a rare event, it was not defined or reported as a primary safety outcome for most of the included studies. There is some residual risk that investigators of included studies may have been more likely to report deaths in DPYD variant carriers as treatment‐related (selective outcome reporting bias). Additionally, it is possible that some treatment‐related deaths may have been misattributed to disease progression (false negatives). We had low confidence in outcome reporting for 6 of the 35 included studies; however, results of a sensitivity analysis excluding these studies did not differ meaningfully from the findings of the main analysis. The generalizability of our findings is also influenced by the included patient population. Most included studies were based in Europe, where these four pathogenic DPYD variants have been best studied.
Conclusion
We found that patients receiving standard doses of fluoropyrimidine chemotherapy who were carriers of pathogenic DPYD gene variants had a 25.6 times increased risk of treatment‐related mortality, with an absolute mortality risk of up to 3.7% for patients carrying any of the c.1905+1G>A, c.1679T>G, or c.2846A>T variants. This information is useful for appraising the clinical utility of DPYD genotyping for preventing severe toxicity and death in patients planned to receive standard‐dose fluoropyrimidine chemotherapy. Together with data from prospective trials showing that fluoropyrimidine dose reductions are protective against severe chemotherapy toxicities in DPYD variant carriers [7, 12, 50], our findings give additional support for the use of DPYD genotyping as an effective tool for identifying patients at risk for fatal toxicity from fluoropyrimidine chemotherapy.
Author Contributions
Conception/design: Bhavina B. Sharma, Karan Rai, Heather Blunt, Tor D. Tosteson, Gabriel A. Brooks
Provision of study material or patients: Gabriel A. Brooks
Collection and/or assembly of data: Bhavina B. Sharma, Karan Rai, Gabriel A. Brooks
Data analysis and interpretation: Bhavina B. Sharma, Karan Rai, Heather Blunt, Wenyan Zhao, Tor D. Tosteson, Gabriel A. Brooks
Manuscript writing: Bhavina B. Sharma, Karan Rai, Gabriel A. Brooks
Final approval of manuscript: Bhavina B. Sharma, Karan Rai, Heather Blunt, Wenyan Zhao, Tor D. Tosteson, Gabriel A. Brooks
Disclosures
The authors indicated no financial relationships.
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Table S1 Detailed data on variant carriers extracted from studies included in systematic review
Acknowledgments
This research was supported by The Dartmouth‐Hitchcock Cancer Research Fellows Program (to G.A.B.), the Cancer Clinical Investigator Team Leadership Award (CCITLA) awarded by the National Cancer Institute (NCI) Coordinating Center for Clinical Trials (to G.A.B.), The Dartmouth Clinical and Translational Science Institute, (under award number UL1TR001086 from the National Center for Advancing Translational Sciences [NCATS] of the National Institutes of Health [NIH]), and the Biostatistics Shared Resource of the Norris Cotton Cancer Center (NCCC) at Dartmouth. The CCITLA and the Biostatistics Shared Resource are funded by NCCC's NCI Cancer Center Support Grant 5P30CA023108‐40). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, NCI, or NCATS.
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Disclosures of potential conflicts of interest may be found at the end of this article.
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Supplementary Materials
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Table S1 Detailed data on variant carriers extracted from studies included in systematic review