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• W2038285492 abstract "Chan JA, Meyerhardt JA, Niedzwiecki D, et al. (Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA). Association of family history with cancer recurrence and survival among patients with stage III colon cancer. JAMA 2008;299:2515–2523. Colorectal cancer (CRC) is among the leading causes of cancer deaths worldwide. Between 16% and 20% of these patients have a first-degree relative with such a neoplasm. In parallel, many studies have demonstrated that the presence of CRC in a first-degree relative increases the risk of developing the disease by 2- or 3-fold (N Engl J Med 1994;331:1669–1674; J Natl Cancer Inst 1994;86:1618–1626; Am J Gastroenterol 2001;96:2992–3003). However, whether a family history of CRC affects the outcome of patients with the established disease was controversial. Indeed, 2 large studies published so far (Int J Epidemiol 1995;24:888–896; Jpn J Clin Oncol 1993;23:342–349) have provided divergent results. Whereas the first did not observe any impact of family history on colon cancer survival, the latter showed that a family history of the disease was associated with a significantly better outcome. Heterogeneity with respect to tumor stage and treatment may explain this difference, at least in part. In this study (JAMA 2008;299:2515–2523), Chan et al prospectively examined the influence of family history of CRC on survival of patients with stage III colon cancer enrolled in a clinical trial of adjuvant therapy. The primary end point of the study was disease-free survival, defined as time from study enrollment to tumor recurrence, occurrence of a new primary colon cancer, or death from any cause. Between April 1999 and May 2001, 1264 patients with stage III colon cancer were enrolled in a large clinical trial of adjuvant chemotherapy sponsored by the National Cancer Institute, which compared therapy with weekly fluorouracil and leucovorin to therapy with weekly irinotecan, fluorouracil, and leucovorin. It is important to mention that no significant differences in overall survival or disease-free survival were observed between both treatment arms (J Clin Oncol 2007;25:3456–3461). Patients were eligible if they had a ECOG performance status of 0 (ie, fully active, able to carry on all predisease performance without restriction) to 2 (ie, ambulatory and capable of all self-care but unable to carry out any work activities; up and about >50% of waking hours), had undergone complete operative resection of the primary tumor, and had regional lymph nodes metastases but no evidence of distant metastases. Of the 1264 patients enrolled, 1177 were given a validated self-administered questionnaire assessing family history of CRC (asking if first-degree relatives—father, mother, or siblings—had history of colon or rectal cancer and the age at first diagnosis), as well as lifestyle habits. Potential confounding prognostic factors were also analyzed (ie, gender, age, race, performance status, body mass index, smoking status, household income, physical activity, treatment arm, tumor location, whether the patient presented with clinical bowel obstruction and/or perforation, tumor differentiation, pT stage, and positive lymph nodes). Moreover, among patients with available tumor specimens, microsatellite instability (MSI) testing and/or immunostaining for the mismatch repair (MMR) proteins MLH1 and MSH2 were also performed. Patients were followed until March 2007 (median, 5.6 years) with a completeness of follow-up of 85%. A total of 1,087 patients were eligible for the study; 195 (17.9%) reported a family history of CRC in ≥1 first-degree relatives. Cancer recurrence or death occurred in 57 of 195 patients (29%) with a family history of CRC and 343 of 892 patients (38%) without a family history. Compared with patients without a family history, the adjusted hazard ratio (HR) among those with 1 or more affected first-degree relatives was 0.72 (95% confidence interval [CI], 0.54–0.96) for disease-free survival, 0.74 (95% CI, 0.55–0.99) for recurrence-free survival, and 0.75 (95% CI, 0.54–1.05) for overall survival. This reduction in risk of cancer recurrence or death associated with a family history became stronger with an increasing number of affected first-degree relatives. Compared with participants without a family history of CRC, those with 1 or ≥2 affected relatives had an adjusted HR of 0.77 (95% CI, 0.57–1.04) and 0.49 (95% CI, 0.23–1.04) for disease-free survival, respectively. Moreover, this benefit in disease-free survival was independent of tumor MSI or MMR status. The authors conclude that among patients with stage III colon cancer who receive adjuvant chemotherapy, the presence of a family history of CRC is associated with a significant reduction in cancer recurrence and death. Even leaving aside the highly penetrant but infrequent hereditary syndromes (1%–5% of all CRC cases), CRC is a neoplasm with a high degree of inheritability (JAMA 2005;293:1986–1994). Indeed, up to one third of patients with CRC report a family history of the disease, thus suggesting that a significant fraction of these tumors are caused by cancer susceptibility genes. In that sense, recent results from genome-wide association studies indicate that several different genomic regions may account for a significant proportion of the familial risk (Nat Genet 2008;40:623–630). The influence of the presence of a family history of CRC on cancer recurrence and survival among patients with established disease, however, has been controversial. In this article (JAMA 2008;299:2515–2523), Chan et al face the topic once again, with a large, prospective, observational study, carefully designed to minimize any particular bias. Of note, only patients with stage III colon cancer were included, and most potential confounding prognostic factors (including tumor MMR status) were evaluated in a very meticulous statistical analysis. These features, along with the fact that it was based on patients enrolled in a National Cancer Institute–sponsored clinical trial, with uniform and standardized treatment and follow-up care, make this study an outstanding investigation. Beyond rare, well-characterized hereditary CRC syndromes (eg, familial adenomatous polyposis or Lynch syndrome), results of this study support the hypothesis that a relatively common, although less penetrant genetic predisposition, may not only influence cancer risk but also patient survival. This intriguing association raises some issues, most of them already addressed by the authors. First, it was likely that patients with colon cancer and a family history of CRC could have a better prognosis because of earlier detection of their disease. To investigate this potential bias, the authors repeated the analysis after excluding patients with earlier tumors (T1 and T2, or N1), and the results remained largely unchanged. In fact, the adjusted HR for cancer recurrence or death among T3–T4 and N2 patients with a family history of CRC was 0.69 and 0.76, respectively, thus demonstrating that the positive impact of CRC family history is independent of earlier detection among these patients. Second, it has been reported that patients whose tumors exhibit MMR deficiency (detected by MSI and/or loss of MMR protein expression) have better prognosis than those with MMR-proficient tumors (J Clin Oncol 2005;23:609–618). To exclude a potential interaction between a family history of CRC and MMR status, Chan et al examined tumor MSI and MLH1/MSH2 protein expression in a substantial subset of patients, in whom tumors were available. The prevalence of MSI tumors was 24% and 15% among patients with and without a family history of CRC, respectively, whereas the corresponding figures for tumors with deficient staining for MMR proteins were 21% and 11%, respectively. However, the results remained unchanged after adjustment for MMR status: The adjusted HR for disease-free survival was 0.73 (95% CI, 0.55–0.97) among patients with a family history of CRC compared with those without a family history. Therefore, the association between nonsyndromic family history of CRC and the reduction in risk of cancer recurrence or death seems to be independent of MMR status. Third, other potential predictors of patient outcome, including adjuvant chemotherapy assignment and lifestyle factors, were also considered and evaluated by means of a multivariate approach. Only age, gender, and tumor location seemed to modify the effect of family history on disease-free survival, being this effect stronger in patients >50 years old, male, and when tumor was located in the right colon. Nevertheless, tests for interaction were not significant. The main result of the study was that cancer recurrence and death was significantly lower among patients with a family history of CRC. Beside this association, there were 2 additional interesting observations. First, the age at which the first-degree relative was diagnosed with CRC (ie, before or after 50 years) did not influence the risk reduction. Second, this reduction became stronger with an increasing number of affected first-degree relatives. In that sense, although only 30 of 195 patients with family history of CRC had ≥2 first-degree relatives affected, a greater reduction of recurrence or death was observed in this subgroup (HR, 0.49). Limitations of this study are few and of questionable relevance. First, family history of CRC was self-reported, thus precluding to definitively rule out a potential misclassification. Second, because only patients with colon cancer were included in the study, it is unknown whether the reduction in risk can be extrapolated to patients with rectal cancer. Third, the study was based on a well-defined cohort enrolled in a clinical trial and, accordingly, it is uncertain if similar results would have been obtained in a clinical practice setting. Nevertheless, the proportion of family history of CRC in this cohort is almost identical to figures obtained in population-based studies and, reasonably, family history should not vary when patients participate in a clinical trial. Finally, and probably the most relevant limitation, this study did not specifically elicit information about the presence of hereditary CRC syndromes (ie, Lynch syndrome), although probably <5% of CRC cases may correspond to these disorders. To solve this issue, germline MMR gene testing should have been performed in patients whose tumors exhibited MSI or loss of protein expression. In summary, a family history of CRC among patients with stage III colon cancer receiving adjuvant chemotherapy seems to be associated with a significant reduction in cancer recurrence and death. If these results were confirmed by other studies of similar characteristics, familial CRC should be definitively considered “a genetics treasure trove for medical discovery,” as defined by Boris Pasche in the accompanying editorial (JAMA 2008;299:2564–2565). On the one hand, it could become a new valuable predictor to identify those patients who would mostly benefit from adjuvant chemotherapy, saving resources and avoiding preventable toxicity. On the other hand, molecular characterization of the subset of patients with family history of CRC might lead to the identification of novel genetic features predictive of response to chemotherapy." @default.
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• W2038285492 title "Family History of Colorectal Cancer: A New Survival Predictor of Colon Cancer?" @default.
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