Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer

Background: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. Materials and methods: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged &lt;40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. Results: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs &lt;30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. Conclusions: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.</p

Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer

Background: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. Materials and methods: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged &lt;40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. Results: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs &lt;30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. Conclusions: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.</p

Dosing oxaliplatin in a haemodialysis patient with metastatic rectum cancer monitored by free platinum concentrations

What is known and objective: Oxaliplatin in combination with fluorouracil and folinic acid is one of the preferred chemotherapeutic options in the treatment of metastatic rectum cancer. However, oxaliplatin is contraindicated in patients with a creatinine clearance <30 mL/min and dosing guidelines in patients on haemodialysis have not been established. Case summary: A 77-year-old haemodialysis patient with metastatic rectum cancer was treated with FOLFOX and bevacizumab (oxaliplatin 70 mg/m2, folinic acid 200 mg/m2, 5-FU 340 mg/m2 bolus and 2040 mg/m2 continuous infusion during 44 hours and bevacizumab 5 mg/kg) every three weeks. Haemodialysis started immediately after infusion of oxaliplatin. The oxaliplatin dose was monitored by measuring free platinum ultrafiltrate concentrations. The AUC0-50 of free platinum plasma ultrafiltrate after cycles 1-3, respectively, was 24.3, 24.7 and 25.8 μg*h/mL. The Cmax was, respectively, 1.3, 1.3 and 2.2 μg/mL. There was no accumulation of free platinum detectable. The patient experienced no toxicity, and after 3 cycles, the CT scan showed a decrease in the liver metastases after which hemihepatectomy and metastasectomy were performed without any complications. A CT scan 6 months after the surgery showed no new liver metastases. However, lymphatic metastasis was diagnosed for which palliative treatment was started. What is new and conclusion: Dosing oxaliplatin in a haemodialysis patient monitored by free platinum concentrations was effective, safe and feasible in clinical practice. Further research is needed to determine the best pharmacokinetic parameter or combination of parameters and corresponding target values to further optimize the oxaliplatin dose for the individual haemodialysis patient

Dosing oxaliplatin in a haemodialysis patient with metastatic rectum cancer monitored by free platinum concentrations

What is known and objective: Oxaliplatin in combination with fluorouracil and folinic acid is one of the preferred chemotherapeutic options in the treatment of metastatic rectum cancer. However, oxaliplatin is contraindicated in patients with a creatinine clearance <30 mL/min and dosing guidelines in patients on haemodialysis have not been established. Case summary: A 77-year-old haemodialysis patient with metastatic rectum cancer was treated with FOLFOX and bevacizumab (oxaliplatin 70 mg/m2, folinic acid 200 mg/m2, 5-FU 340 mg/m2 bolus and 2040 mg/m2 continuous infusion during 44 hours and bevacizumab 5 mg/kg) every three weeks. Haemodialysis started immediately after infusion of oxaliplatin. The oxaliplatin dose was monitored by measuring free platinum ultrafiltrate concentrations. The AUC0-50 of free platinum plasma ultrafiltrate after cycles 1-3, respectively, was 24.3, 24.7 and 25.8 μg*h/mL. The Cmax was, respectively, 1.3, 1.3 and 2.2 μg/mL. There was no accumulation of free platinum detectable. The patient experienced no toxicity, and after 3 cycles, the CT scan showed a decrease in the liver metastases after which hemihepatectomy and metastasectomy were performed without any complications. A CT scan 6 months after the surgery showed no new liver metastases. However, lymphatic metastasis was diagnosed for which palliative treatment was started. What is new and conclusion: Dosing oxaliplatin in a haemodialysis patient monitored by free platinum concentrations was effective, safe and feasible in clinical practice. Further research is needed to determine the best pharmacokinetic parameter or combination of parameters and corresponding target values to further optimize the oxaliplatin dose for the individual haemodialysis patient

Survival of Patients With Cancer With DPYD Variant Alleles and Dose-Individualized Fluoropyrimidine Therapy-A Matched-Pair Analysis

PURPOSE DPYD-guided fluoropyrimidine dosing improves patient safety in carriers of DPYD variant alleles. However, the impact on treatment outcome in these patients is largely unknown. Therefore, progression-free survival (PFS) and overall survival (OS) were compared between DPYD variant carriers treated with a reduced dose and DPYD wild-type controls receiving a full fluoropyrimidine dose in a retrospective matched-pair survival analysis. METHODS Data from a prospective multicenter study (ClinicalTrials.gov identifier: NCT02324452) in which DPYD variant carriers received a 25% (c.1236G&gt;A and c.2846A&gt;T) or 50% (DPYD*2A and c.1679T&gt;G) reduced dose and data from DPYD variant carriers treated with a similarly reduced dose of fluoropyrimidines identified during routine clinical care were obtained. Each DPYD variant carrier was matched to three DPYD wild-type controls treated with a standard dose. Survival analyses were performed using Kaplan-Meier estimates and Cox regression. RESULTS In total, 156 DPYD variant carriers and 775 DPYD wild-type controls were available for analysis. Sixty-one c.1236G&gt;A, 25 DPYD*2A, 13 c.2846A&gt;T, and—when pooled—93 DPYD variant carriers could each be matched to three unique DPYD wild-type controls. For pooled DPYD variant carriers, PFS (hazard ratio [HR], 1.23; 95% CI, 1.00 to 1.51; P 5 .053) and OS (HR, 0.95; 95% CI, 0.75 to 1.51; P 5 .698) were not negatively affected by DPYD-guided dose individualization. In the subgroup analyses, a shorter PFS (HR, 1.43; 95% CI, 1.10 to 1.86; P 5 .007) was found in c.1236G&gt;A variant carriers, whereas no differences were found for DPYD*2A and c.2846A&gt;T carriers. CONCLUSION In this exploratory analysis, DPYD-guided fluoropyrimidine dosing does not negatively affect PFS and OS in pooled DPYD variant carriers. Close monitoring with early dose modifications based on toxicity is recommended, especially for c.1236G&gt;A carriers receiving a reduced starting dose.</p