The risk of severe irinotecan-induced neutropenia has been shown to be related to the UGT1 variant UGT1A1*28, which increases exposure to the potent metabolite SN-38. Our goal was to identify a novel UGT1 marker(s) using 28 haplotype-tagged single nucleotide polymorphisms genotyped by mass spectrometry. By characterizing the UGT1 sequence from a cohort of 167 Canadian metastatic colorectal cancer (mCRC) patients and a validation cohort of 250 Italian mCRC patients, we found rs11563250G, located in the intergenic region downstream of UGT1, to be significantly associated with reduced risk of severe neutropenia (odds ratio (OR)=0.21; p=0.043 and OR=0.27; p=0.036, respectively, and OR=0.31 when combined; p=0.001), which remained significant upon correction for multiple testing in the combined cohort (p=0.041). For the two-marker haplotype rs11563250G and UGT1A1*1 (rs8175347 TA6), the OR was of 0.17 (p=0.0004). Genetic testing of this marker may identify patients who might benefit from increased irinotecan dosing.
Purpose:
Neoadjuvant chemotherapy may provide early indication of treatment response. Pathologic complete response (pCR) rate is a surrogate measure of disease-free and overall survival. Anthracycline remain an important component of chemotherapy
regimen for breast cancer (BC), while adding taxane confers additional pCR rate. However the combination of anthracycline and trastuzumab remain controversial due to potential increased risk of cardiac event. This trial was designed to compare the efficacy and safety between epirubicin(E) and carboplatin(C) in combination with paclitaxel(P) and trastuzumab(H).
Methods:
In 13 medical centers, 100 Patients with HER-2/neu immunohistochemistry (IHC) 3+ or FISH-amplified untreated breast cancer, baseline left ventricular ejection fraction (LVEF) of ≥ 55%, ECOG0/1, were enrolled from Sep 2011 to May 2012. Study medication was as follows: Trastuzumab (4 mg/kg loading dose followed by 2 mg/kg) and Pacitaxel (75 mg/m2) weekly combine with Carbopatin (AUC 2) weekly for PCH group or Epirubicin(75 mg/m2) every 3 weeks for PEH group. Patients were recommended to receive 4 or more cycles. The primary endpoint was pCR in the breast and axilla. Secondary endpoints included clinical response, safety.
Results:
By Aug 16, 2012, 50 patients were randomly assigned to receive PCH regimen and 50 to receive PEH regimen. 49 belonged to TNM stage II, 51 belonged to TNM stage III. The median age was 48 years (range 29 to 65 years). 87 patients completed at least 4 cycles neoadjuvant therapy and then received surgical treatment. pCR in the breast/axilla were found in 38 patients (43.7%; 95% confidence interval [CI]: 33.3%-54.1%). There was no statistic significant difference in PCH and PEH regimen (39.1% vs. 48.8%; p = 0.365). However, PEH regimen achieved significant higher pCR in luminal-B (HER2-poitive) subgroup compared with PCH regimen (55.0% vs. 24.0%; p = 0.033), but not in ERBB2+ subgroup (42.9% vs. 57.1%; p = 0.355). Median LVEF at baseline was 66.0% (range 56.5% to 83.0%), having was no difference between PCH and PEH group (67.0% vs. 65.0%). After 2 cycles in 82 patients, the median LVEF was 64.7% (range 55.0% to 84.0%), there was no difference of LVEF (63.0% vs.66.0%). After 4 cycles in 80 patients, the median LVEF was 66.0% (range 53.0% to 76.0%), no difference was observed between PCH and PEH group (63.0% vs. 66.2%). 8 patients had LVEF decreases of over 10% after 2 cycles, of which 5 patients in PCH group and 3 patients in PEH group. After more than 4 cycles, 3 patients in PCH group and 1 patient in PEH group had LVEF decreases of over 10.0% compared with baseline. No patient experienced LVEF of less than 50% and congestive heart failure (CHF). There was no cardiac death reported.
Conclusion:
Both PCH and PEH regimens as neoadjuvant chemotherapy have the similar pCR rate for breast cancer patients with HER2-overexpression. PEH might improve the possibility of eradicating invasive cancer in the breast and axilla, especially in the luminal-B (HER2-positive) subtype. PEH is feasible and is not likely to increase the incidence of acute cardiac events compared to PCH.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-17.
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