Influence of chemotherapeutic drug-related gene polymorphisms on toxicity and survival of early breast cancer patients receiving adjuvant chemotherapy.

BACKGROUND: We investigated whether GSTT1 ("null" allele), GSTM1 ("null"allele), GSTP1 (A313G), RFC1 (G80A), MTHFR (C677T), TS (2R/3R) polymorphisms were associated with toxicity and survival in patients with early breast cancer (EBC) treated with adjuvant chemotherapy (CT). METHODS: This prospective trial included patients with stage I-III BC subjected to CT with CMF or FEC regimens. PCR-RFLP was performed for MTHFR, RFC1 and GSTP1, while PCR for TS, GSTT1 and GSTM1 genes. RESULTS: Among the 244 patients consecutively enrolled, 48.7% were treated with FEC and 51.3% with CMF. Patients with TS2R/3R genotype showed less frequently severe neutropenia (G3/G4) than those with TS2R/2R and 3R/3R genotype (p = 0.038). Patients with MTHFRCT genotype had a higher probability of developing severe neutropenia than those with MTHFR CC genotype (p = 0.043). Patients with RFC1GG or GSTT1-null genotype or their combination (GSTT1-null/RFC1GG) were significantly associated with a shorter disease free survival (DFS) (p = 0.009, p = 0.053, p = 0.003, respectively) and overall survival (OS) (p = 0.036, p = 0.015, p = 0.005, respectively). Multivariate analysis confirmed the association of RFC1GG genotype with a shorter DFS (p = 0.018) and of GSTT1-null genotype of a worse OS (p = 0.003), as well as for the combined genotypes GSTT1-null/RFC1GG, (DFS: p = 0.004 and OS: p = 0.003). CONCLUSIONS: Our data suggest that TS2R/2R and 3R/3R or MTHFR CT genotypes have a potential role in identifying patients with greater risk of toxicity to CMF/FEC and that RFC1 GG and GSTT1-null genotypes alone or in combination could be important markers in predicting clinical outcome in EBC patients.

Adjuvant chemotherapy in completely resected gastric cancer: a randomized phase III trial conducted by GOIRC.

BACKGROUND: Complete surgical resection of gastric cancer is potentially curative, but long-term survival is poor. METHODS: Patients with histologically proven adenocarcinoma of the stomach of stages IB, II, IIIA and B, or IV (T4N2M0) and treated with potentially curative surgery were randomly assigned to follow-up alone or to intravenous treatment with four cycles (repeated every 21 days) of PELF (cisplatin [40 mg/m(2), on days 1 and 5], epirubicin [30 mg/m(2), days 1 and 5], L-leucovorin [100 mg/m(2), days 1-4], and 5-fluorouracil [300 mg/m(2), days 1-4] in a hospital setting. Frequencies and severity of adverse events were determined. Overall survival (OS) and disease-free survival (DFS) were compared between the treatment arms using Kaplan-Meier analysis and a Cox proportional hazards regression model. All statistical tests were two-sided. RESULTS: From January 1995 through September 2000, 258 patients were randomly assigned to chemotherapy (n = 130) or surgery alone (n = 128). Patient characteristics were well balanced between the two arms. Among those who received chemotherapy, grade 3 or 4 toxic effects including vomiting, mucositis, and diarrhea were experienced by 21.1%, 8.4%, and 11.8% of patients, respectively. Leucopenia, anemia, and thrombocytopenia of grade 3 or 4 were experienced by 20.3%, 3.3%, and 4.2% of patients, respectively. After a median follow-up of 72.8 months, 128 patients (49.6%) experienced recurrence and 139 (53.9%) deaths were observed, one toxicity-related. Relative to treatment with surgery alone, adjuvant chemotherapy did not increase disease-free survival (hazard ratio [HR] of recurrence = 0.92; 95% confidence interval [CI] = 0.66 to 1.27) or overall survival (HR of death = 0.90; 95% CI = 0.64 to 1.26). CONCLUSIONS: Our results failed to provide proof of an effect of adjuvant chemotherapy with PELF on overall survival or disease-free survival. The estimated effect of chemotherapy (10% reduction in the hazard of death or relapse) is modest and consistent with the results of meta-analyses of adjuvant chemotherapy without platinum agents.

HER2 overexpression as a predictive marker in a randomized trial comparing adjuvant cyclophosphamide/methotrexate/5-fluorouracil with epirubicin in patients with stage I/II breast cancer: long-term results.

BACKGROUND: HER2 overexpression/amplification has been reported to be a predictor of prognosis in breast cancer and a potential marker for selecting the optimal adjuvant chemotherapy. PATIENTS AND METHODS: HER2 expression and its interaction with treatment were retrospectively evaluated in 266 of 348 patients in a trial comparing adjuvant CMF (cyclophosphamide/methotrexate/5-fluorouracil) with weekly epirubicin in stage I/II breast cancer. HER2 expression was determined by immunohistochemistry (IHC) using the monoclonal antibody CB11. Initially, any cell showing definite membrane staining was counted, and HER2 overexpression was analyzed as a continuous variable and as a dichotomous variable, with a cutoff of > 50% of positively stained cells. Subsequently, the same slides were reanalyzed with the HercepTest. RESULTS: Of the 266 tumors immunostained for HER2, 34% exhibited nearly homogeneous staining with > 50% positive cells. When the HercepTest was applied, 8% of tumors were IHC 3+ and 8% were IHC 2+. At 8 years, no statistically significant difference in relapse-free survival (RFS) and overall survival (OS) was observed between the treatment arms in patients with low versus high HER2 overexpression, although the number of events is low. The OS was statistically shorter in patients with high HER2 overexpression in the CMF arm, whereas no difference was observed in the epirubicin arm, suggesting that patients whose cancer overexpresses HER2 could benefit more from anthracycline-based therapy. CONCLUSION: HER2 overexpression was associated with a poorer OS but not a poorer RFS. However, a Cox regression model did not confirm the prognostic role of HER2 for OS.

The multidisciplinary rectal cancer treatment: main convergences, controversial aspects and investigational areas which support the need for an European Consensus.

BACKGROUND AND PURPOSE: During the past decades staging and treatment of rectal cancer are used different in Europe and in North America. To promote a process to integrate the daily practice with the best evidence of the literature an International Conference was organized in Italy. Agreement between Experts, Centres, and specialists who participated in the Conference are reported. METHODS: Five aspects were analyzed and a questionnaire was tailored for this purpose. The questionnaire had 159 questions. During the Conference, at the beginning of each Session, the moderators showed the answers from the Experts and the Centres, and, at the end of the session, the audience voted in all controversial issues. Agreements were scored at three levels: minimum, if it was between 51 and 74% of votes for each group; moderate, between 75 and 94%; large, more than 94%. RESULTS: The main results are: staging: endoanal ultrasound was considered as mandatory in T staging, in the evaluation of sphincter infiltration, and in the restaging of T after chemoradiotherapy (chRT). Magnetic Resonance Imaging is mandatory in the evaluation of mesorectal fascia infiltration. Endoscopy had a moderate agreement for the definition of tumour location, and the barium enema as optional. Digital rectal examination is complementary for staging and PET-CT investigational for T, N and yT staging. Preoperative radiotherapy: for T4 stage chRT was always the preferred treatment, often with moderate agreement, for any tumour location and N status. For T3, chRT received the same agreement except for high location and N0-N1. For T2 stage, N2 and positive nodes outside the mesorectum, chRT received minimum agreement for low and middle tumours; for high tumours only positive nodes outside the mesorectum was agreed upon. Preoperative radiotherapy, negative specimen and sphincter preservation: chRT was agreed by many for all T stages and N presentations of lower third tumours, except for T1-2 N0-N1. Postoperative treatments: the selection for these treatments often received moderate agreement according to the infiltration of surrounding organs, positive nodal status and circumferential radial margins. Therapy of metastatic disease: an agreement was found for FOLFOX as first-line therapy and for FOLFIRI as second-line, although comparative studies show similar activity of FOLFOX and FOLFIRI regimens. CONCLUSIONS: This process represents an expertise opinion process that may contribute to increased scientific debate and to promote the development of 'guidelines', 'clinical recommendations' and ultimately a Consensus on the evolving approach to rectal cancer treatment.