No abstract

There is growing evidence that common variants of the transforming growth factor-beta (TGF-beta) signaling pathway may modify breast cancer risk. In vitro studies have shown that some variants increase TGF-beta signaling, whereas others have an opposite effect. We tested the hypothesis that a combined genetic assessment of two well-characterized variants may predict breast cancer risk. Consecutive patients (n = 660) with breast cancer from the Memorial Sloan-Kettering Cancer Center (New York, NY) and healthy females (n = 880) from New York City were genotyped for the hypomorphic TGFBR1*6A allele and for the TGFB1 T29C variant that results in increased TGF-beta circulating levels. Cases and controls were of similar ethnicity and geographic location. Thirty percent of cases were identified as high or low TGF-beta signalers based on TGFB1 and TGFBR1 genotypes. There was a significantly higher proportion of high signalers (TGFBR1/TGFBR1 and TGFB1*CC) among controls (21.6%) than cases (15.7%; P = 0.003). The odds ratio [OR; 95% confidence interval (95% CI)] for individuals with the lowest expected TGF-beta signaling level (TGFB1*TT or TGFB1*TC and TGFBR1*6A) was 1.69 (1.08-2.66) when compared with individuals with the highest expected TGF-signaling levels. Breast cancer risk incurred by low signalers was most pronounced among women after age 50 years (OR, 2.05; 95% CI, 1.01-4.16). TGFBR1*6A was associated with a significantly increased risk for breast cancer (OR, 1.46; 95% CI, 1.04-2.06), but the TGFB1*CC genotype was not associated with any appreciable risk (OR, 0.89; 95% CI, 0.63-1.21). TGFBR1*6A effect was most pronounced among women diagnosed after age 50 years (OR, 2.20; 95% CI, 1.25-3.87). This is the first study assessing the TGF-beta signaling pathway through two common and functionally relevant TGFBR1 and TGFB1 variants. This approach may predict breast cancer risk in a large subset of the population.

Capecitabine is used to treat advanced breast and gastrointestinal malignancies. A single case of encephalopathy and three cases of peripheral neuropathy are the only neurotoxicities reported. The authors report five additional cases of capecitabine-induced multifocal leukoencephalopathy.

An estimated 106,370 new cases of colon cancer were forecast to be diagnosed in the U. S. in 2004 [1]. Of these cases, approximately a quarter were predicted to be stage II disease. The overall survival rate for stage II patients after surgery alone ranges from 70%-80% [2]. Adjuvant chemotherapy has been shown to improve survival in patients with node-positive or stage III colon cancer in many studies [3][4][5]. The benefit of adjuvant therapy for patients with stage II colon cancer has been an area of controversy. Recently, the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) published guidelines based on a thorough analysis of the available data [6][7][8]. The purpose of this article is to review the trials that have contributed to the current recommendations regarding adjuvant therapy for stage II colon cancer patients and to summarize recommendations.Staging in colorectal cancer has recently undergone revision to better reflect the differences in survival within stages II and III [9]. Stage II has been subdivided into IIA (T3N0) and IIB (T4N0). The 5-year disease-free survival (DFS) rate with surgery alone for stage IIA patients is 65%-73% (highgrade versus low-grade lesions), and it is 51%-60% for stage IIB patients (high-grade versus low-grade lesions) [10]. Stage III has also been subdivided to reflect differences in 5-year survival rates depending on depth of invasion as well as the number of lymph nodes involved. In a secondary analysis of the data from the Intergroup 0089 trial (INT-0089) of high-risk, stage II and stage III colon cancer patients, the number of lymph nodes analyzed was found to be an independent prognostic variable [11]. Whether lymph nodes were found to be positive or negative, survival increased as the number of lymph nodes analyzed increased (p = .0001 and p = .0005, respectively, for stage III and II disease).

Lessons Learned. Adding docetaxel to the modified FOLFOX7 backbone (DOF) is a feasible three‐drug combination therapy for advanced gastric cancer with high activity, providing evidence that leucovorin is not necessary in this setting. The DOF regimen represents an alternative to the FLOT (5‐FU 2,600 mg/m 2 as 24‐hour infusion with leucovorin 200 mg/m 2 , oxaliplatin 85 mg/m 2 , and docetaxel 50 mg/m 2 ) regimen that can be considered in select patients with advanced gastric cancer and is a potential choice in the curative setting. Background. The combination of docetaxel, cisplatin, and 5‐fluorouracil (5‐FU) demonstrates high response rates in advanced gastric cancer, albeit with increased toxicity. Given the efficacy of platinum‐taxane‐fluoropyrimidine regimens, this phase II study evaluated the efficacy and toxicity of docetaxel, oxaliplatin, and 5‐FU (DOF) for the treatment of metastatic or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinoma. Methods. Patients with metastatic or unresectable gastric or GEJ adenocarcinoma with no prior therapy for metastatic disease received docetaxel 50 mg/m 2 on day 1, oxaliplatin 85 mg/m 2 on day 1, and 5‐FU 2,400 mg/m 2 continuous intravenous infusion over 46 hours; cycles were repeated every 2 weeks. The primary endpoint was overall response rate (ORR). Results. Forty‐four patients were enrolled. Assessment of treatment response and toxicity was feasible in 41 and 43 patients, respectively. ORR was 73.2% (68.3% partial response; 4.9% complete response). Therapy was discontinued for progressive disease in 53%, toxicity in 26%, and death on treatment in 16%. Two patients underwent surgical resection. Thirty‐three patients (76.7%) received at least seven cycles (7–34). Grade 3–4 toxicities occurred in 31 patients (72.1%), including neutropenia (23.3%), neurologic (20.9%), and diarrhea (14.0%). Median overall survival was 10.3 months. Conclusion. DOF demonstrates a high response rate, expected safety profile, and prolonged survival and remains an option for select patients with unresectable or metastatic gastric or GEJ adenocarcinoma.