The GSTP1 Ile(105)Val polymorphism is associated in a dose-dependent fashion with increased survival of patients with advanced colorectal cancer receiving 5-FU/oxaliplatin chemotherapy.

Thymidylate synthase is a target enzyme for chemotherapeutic agents such as 5-fluorouracil and capecitabine, its oral prodrug. The human thymidylate synthase gene promoter is polymorphic, having either double or triple repeats of a 28-bp sequence. It has previously been shown that colorectal cancer patients who are homozygous for the triple tandem repeats (L/L) have significantly higher thymidylate synthase mRNA expression than those homozygous for the double repeat variant (S/S). Capecitabine is converted to 5-fluorouracil by a sequential triple enzyme pathway, with the last step catalyzed by the tumor-associated angiogenic factor thymidine phosphorylase. We have recently shown that individuals with metastatic colorectal cancer treated with 5-fluorouracil have a higher response rate if they are homozygous for the genotype S/S as opposed to S/L or L/L. Our hypothesis is that individuals homozygous for the double repeat variant (S/S) should have a better response to capecitabine than their counterparts with S/L or L/L. In this retrospective pilot study we assessed the thymidylate synthase polymorphic status of 24 patients with metastatic colorectal cancer and determined their response to capecitabine. We found that 75% (3/4) of individuals with the S/S variant responded to capecitabine, compared to 8% (1/12) and 25% (2/8) of those with the S/L and L/L variants, respectively. Our data suggest that genotyping patients for the thymidylate synthase polymorphism would be useful in identifying patients who are more likely to respond to capecitabine treatment for advanced colorectal cancer.

IMPORTANCE Deficiencies in advance care planning and symptom management are associated with avoidable acute care use among patients with cancer. Community health worker (CHW)-led approaches may be an approach to reduce acute care use but remain untested in community settings.OBJECTIVE To determine whether a CHW-led advance care planning and symptom screening intervention can reduce acute care use more than usual care in a community setting.DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial was conducted among patients with newly diagnosed advanced-stage or recurrent solid and hematologic cancers from August 8, 2017, through November 30, 2021. Data analysis was performed November 30, 2021, through January 1, 2022, by intention to treat.INTERVENTIONS Participants were randomized 1:1 to usual care (control group) or usual care with the 6-month CHW-led intervention (intervention group). MAIN OUTCOMES AND MEASURESThe primary outcome was acute care use. Secondary outcomes included advance care planning documentation, supportive care use, patient-reported outcomes, survival, and end-of-life care use. RESULTS Among 128 participants, median (range) age was 67 (19-89) years; 61 (47.7%) were female; and 2 (1.6%) were American Indian or Alaska Native, 11 (8.6%) were Asian, 5 (3.9%) were Black, 23 (18.0%) were Hispanic or Latino, 2 (1.6%) were of mixed race, 2 (1.6%) were Native Hawaiian or other Pacific Islander, 86 (67.2%) were White, and 20 (15.6%) did not report race. Intervention participants had 62% lower risk of acute care use than the control (hazard ratio, 0.38; 95% CI, 0.19-0.76) within 6 months. At 12 months, intervention participants had 17% lower odds of acute care use (odds ratio [OR], 0.83; 95% CI, 0.69-0.98), 8 times the odds of advance care planning documentation (OR, 7.18; 95% CI, 2.85-18.13), 4 times the odds of palliative care (OR, 4.46; 95% CI,, nearly double the odds of hospice (OR, 1.83; 95% CI, 1.16-2.88), and nearly double the odds of improved mental and emotional health from enrollment to 6 and 12 months postenrollment (OR, 1.82; 95% CI, 1. and OR, 2.20; 95% CI,, respectively) than the control. There were no differences in the death (control, 26 [40.6%] vs intervention, 32 [50.0%]). Fewer intervention participants had acute care use (0 vs 6 [23.1%]) in the month before death than the control. CONCLUSIONS AND RELEVANCEIn this randomized clinical trial, integration of a CHW-led intervention into cancer care reduced acute care use and is one approach to improve cancer care delivery for patients with advanced stages of disease in community settings.

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