Trastuzumab (herceptin) is an effective drug for human epidermal growth factor receptor type 2 (HER2)-positive cancer. However, cardiotoxicity remains a serious complication. In our previous genome-wide association study (GWAS), we identified potential associations for five single nucleotide polymorphisms (SNPs) with trastuzumab-induced cardiotoxicity in a Japanese population. To validate this association, here we performed replication studies using Japanese and Singaporean case-control cohorts (Japan: 6 cases and 206 controls; Singapore: 22 cases and 178 controls). Although none of the SNPs showed a statistically significant association with trastuzumab-induced cardiotoxicity, we show that three (rs8032978, rs7406710 and rs9316695) and four (rs8032978, rs7406710, rs28415722 and rs11932853) SNPs had an effect in the same direction in the Japanese and the Singaporean cohort, respectively, as that in our previous study. Combining the previous study with the current replication studies, we find a strong association for two SNPs, rs8032978 and rs7406710, with trastuzumab-induced cardiotoxicity (Pcombined = 4.92 × 10-5 and 5.50 × 10-5, respectively). These data suggest that rs8032978 and rs7406710 could be predictive markers of trastuzumab-induced cardiotoxicity in Japanese and Singaporean populations, and support their potential use in clinical risk assessment. These findings offer a first step toward the development of clinically available markers for the potential risk of trastuzumab-induced cardiotoxicity as well as an improved understanding of the pathogenesis of this complication.
The hypothesis that breast cancer (BC) susceptibility variants are linked to chemotherapy-induced toxicity has been previously explored. Here, we investigated the association between a validated 313-marker-based BC polygenic risk score (PRS) and chemotherapy-induced neutropenia without fever and febrile neutropenia (FNc) in Asian BC patients.This observational case-control study of Asian BC patients treated with chemotherapy included 161 FNc patients, 219 neutropenia patients, and 936 patients who did not develop neutropenia. A continuous PRS was calculated by summing weighted risk alleles associated with overall, estrogen receptor- (ER-) positive, and ER-negative BC risk. PRS distributions neutropenia or FNc cases were compared to controls who did not develop neutropenia using two-sample t-tests. Odds ratios (OR) and corresponding 95% confidence intervals were estimated for the associations between PRS (quartiles and per standard deviation (SD) increase) and neutropenia-related outcomes compared to controls.PRS distributions were not significantly different in any of the comparisons. Higher PRSoverall quartiles were negatively correlated with neutropenia or FNc. However, the associations were not statistically significant (PRS per SD increase OR neutropenia: 0.91 [0.79-1.06]; FNc: 0.87 [0.73-1.03]). No dose-dependent trend was observed for the ER-positive weighted PRS (PRSER-pos) and ER-negative weighted PRS (PRSER-neg).BC PRS was not strongly associated with chemotherapy-induced neutropenia or FNc.
With greater awareness and increased screening, cancers are increasingly being diagnosed at stage I. Women with these small node-negative tumours have excellent survival prospects after surgery, but many women, especially those with triple-negative and human epidermal growth factor receptor (HER)-2-positive tumours, still receive adjuvant systemic treatments to reduce the recurrence risk. We review the outcomes of women diagnosed with stage I (T1N0M0) tumours in our unit and examine the effect of systemic chemotherapy with/without targeted therapy on recurrence patterns and survival outcomes. We reviewed 643 women diagnosed with T1N0M0 disease over a 10-year period. Five-year recurrence-free survival (RFS) was 96.6% and the 10-year RFS was 95.5%. Recurrence occurred in 4.7% of the women and was limited to locoregional sites in two-thirds of the instances. Systemic recurrences developed in 12 women, all of whom had ER-positive/HER2-negative disease. The mode of surgery emerged as the only independent predictor of recurrence. Recurrence was highest in women treated with wide local excision (WLE) alone (p < 0.05), but not in those who had received breast radiation after WLE (p = 0.112). Systemic chemotherapy, with or without anti-HER2 therapy, was discussed with 334 women, of whom 50.6% received the treatment; these women were more often younger and had triple-negative or HER2-positive tumours (p < 0.001). Women who received chemotherapy showed a non-significant tendency to develop locoregional recurrence (p = 0.104), but the number of systemic recurrences were similar to those documented in women who had not received chemotherapy. Chemotherapy and/or targeted treatment was not observed to have a significant effect on 5-year recurrence-free survival (p = 0.444). Stage I cancers have excellent survival outcomes. An optimal local surgical treatment is important and we did not find chemotherapy and/or targeted therapy to produce any significant differences in survival.
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