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Original Contribution |

Association of Family History With Cancer Recurrence and Survival Among Patients With Stage III Colon Cancer FREE

Jennifer A. Chan, MD, MPH; Jeffrey A. Meyerhardt, MD, MPH; Donna Niedzwiecki, PhD; Donna Hollis, MS; Leonard B. Saltz, MD; Robert J. Mayer, MD; James Thomas, MD, PhD; Paul Schaefer, MD; Renaud Whittom, MD; Alexander Hantel, MD; Richard M. Goldberg, MD; Robert S. Warren, MD; Monica Bertagnolli, MD; Charles S. Fuchs, MD, MPH
[+] Author Affiliations

Author Affiliations: Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts (Drs Chan, Meyerhardt, Mayer, and Fuchs); Cancer and Leukemia Group B (CALGB) Statistical Center, Duke University Medical Center, Durham, North Carolina (Dr Niedzwiecki and Ms Hollis); Memorial Sloan-Kettering Cancer Center, New York, New York (Dr Saltz); Ohio State University, Columbus (Dr Thomas); Toledo Community Hospital Oncology Program Community Clinical Oncology Program, Toledo, Ohio (Dr Schaefer); Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada (Dr Whittom); Loyola University Stritch School of Medicine, Maywood, Illinois (Dr Hantel); Department of Hematology/Oncology, University of North Carolina, Chapel Hill (Dr Goldberg); Division of Surgical Oncology, University of California at San Francisco (Dr Warren); and Division of Surgical Oncology, Brigham and Women's Hospital, Boston (Dr Bertagnolli).


JAMA. 2008;299(21):2515-2523. doi:10.1001/jama.299.21.2515.
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Context A family history of colorectal cancer in a first-degree relative increases the risk of developing colorectal cancer. However, the influence of family history on cancer recurrence and survival among patients with established disease remains uncertain.

Objective To examine the association of family history of colorectal cancer with cancer recurrence and survival of patients with colon cancer.

Design, Setting, and Participants Prospective observational study of 1087 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial (CALGB 89803) between April 1999 and May 2001. Patients provided data on family history at baseline and were followed up until March 2007 for disease recurrence and death (median follow-up, 5.6 years). In a subset of patients, we assessed microsatellite instability (MSI) and expression of the mismatch repair (MMR) proteins MLH1 and MSH2 in tumor specimens.

Main Outcome Measures Disease-free survival, recurrence-free survival, and overall survival according to the presence or absence of a family history of colorectal cancer.

Results Among 1087 eligible patients, 195 (17.9%) reported a family history of colorectal cancer in a first-degree relative. Cancer recurrence or death occurred in 57 of 195 patients (29%; 95% confidence interval [CI], 23%-36%) with a family history of colorectal cancer and 343 of 892 patients (38%; 95% CI, 35%-42%) without a family history. Compared with patients without a family history, the adjusted hazard ratios (HRs) among those with 1 or more affected first-degree relatives were 0.72 (95% 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 colorectal cancer, those with 1 affected relative had a multivariate HR of 0.77 (95% CI, 0.57-1.04) for disease-free survival. For participants with 2 or more affected relatives, we observed a greater reduction in risk (multivariate HR for disease-free survival, 0.49; 95% CI, 0.23-1.04; P for trend with increasing number of affected relatives = .01). The improved disease-free survival associated with a family history was independent of tumoral MSI or MMR status.

Conclusion Among patients with stage III colon cancer receiving adjuvant chemotherapy, a family history of colorectal cancer is associated with a significant reduction in cancer recurrence and death.

Figures in this Article

Approximately 16% to 20% of patients with colorectal cancer have a first-degree relative with colorectal cancer.1 Beyond rare but highly penetrant hereditary colorectal cancer syndromes, numerous studies have demonstrated that a history of colorectal cancer in a first-degree relative increases the risk of developing the disease by approximately 2-fold.25 However, the influence of family history on cancer recurrence and survival among patients with established colon cancer remains uncertain. A study of the Utah Population Database and Cancer Registry observed that family history of colon cancer had little impact on colon cancer patient survival6; in contrast, an analysis of a Japanese tumor registry demonstrated an improved prognosis.7 Interpretation of these conflicting data is limited by a lack of detailed information regarding tumor stage and treatment in either of these studies.

We therefore prospectively examined the influence of family history of colorectal cancer on survival of patients with stage III colon cancer who participated in a large clinical trial of adjuvant chemotherapy sponsored by the National Cancer Institute (NCI). Because detailed information about family history of colorectal cancer was assessed at study entry, we were able to prospectively analyze the influence of family history while adjusting for other predictors of cancer recurrence and survival. In addition, among a subset of subjects with archived tumor specimens, we were able to assess whether the association between family history and survival was independent of tumoral microsatellite instability (MSI) or expression of mismatch repair (MMR) proteins.

Study Population

Patients in this study were participants in the NCI-sponsored Cancer and Leukemia Group B (CALGB) adjuvant therapy trial for stage III colon cancer (CALGB 89803). This study was a randomized trial comparing therapy with weekly fluorouracil and leucovorin to therapy with weekly irinotecan, fluorouracil, and leucovorin.8 Between April 1999 and May 2001, 1264 patients were enrolled in the treatment trial. As part of the original randomized clinical trial protocol, we included a plan to study diet, lifestyle, and family history on patient survival. A validated self-administered questionnaire assessing diet and lifestyle habits as well as family history of colorectal cancer was administered to patients midway through their adjuvant therapy (4 months after surgical resection).9,10

The protocol amendment to survey family history was activated after the first 87 patients were enrolled; therefore, only the subsequent 1177 patients were offered the diet and lifestyle companion study. An additional 59 patients experienced cancer recurrence, death, or removal from the protocol before receiving the questionnaire. Thus, 1118 patients were eligible to complete the questionnaire, of whom 1095 patients (98%) completed the survey. Consistent with prior analyses, we excluded patients who experienced cancer recurrence or death within 90 days of trial enrollment to avoid potential bias in risk-factor assessment related to underlying illness,9 thus leaving 1087 patients eligible for analysis. Figure 1 illustrates adherence with completion of the questionnaire and derivation of the final sample size.

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Figure 1. Derivation of Cohort Size
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CALGB indicates Cancer and Leukemia Group B.

Patients were eligible for the treatment trial (and thus this companion study) if they had undergone a complete surgical resection of the primary tumor within 56 days of study entry and had regional lymph node metastases but no evidence of distant metastases (stage III colon cancer). Patients were required to have a baseline Eastern Cooperative Oncology Group performance status of 0 to 2 (ambulatory) and have adequate bone marrow, renal, and hepatic function. Race or ethnicity was self-reported and recorded in the hospital database at each participating center. Classifications included white, Hispanic, black, Asian, Native Hawaiian, Native American, Indian, Filipino, other, and unknown. These data along with other demographic information were reported by each participating center to the CALGB Statistical Center. All patients provided written informed consent, approved by the institutional review board of each participating institution.

Family History Assessment

Participants were asked, “Have any of the following relatives (father, mother, 1 sibling, additional sibling) had colon or rectal cancer?” with an option for yes or no for each relative. Patients were instructed to include any deceased relative and not count half-siblings. Additionally, for each affected relative, patients provided information about the decade of the relative's age at first diagnosis (<50 years, 50-59 years, 60-69 years, ≥70 years, age unknown). No questions were asked about family size, and no attempt was made to validate reports of cancer in family members.

Measurement of MSI

Among patients with available tumor specimens, DNA was extracted from paraffin-embedded tumor and nontumor tissue. Polymerase chain reaction analysis was conducted using a panel of 10 DNA mononucleotide and dinucleotide microsatellite markers.11 Only cases with 5 or more evaluable microsatellite markers were included. Those showing instability in at least 40% of the loci tested were classified as having high-frequency MSI (MSI-H). Cases with no evaluable markers showing instability were classed as microsatellite stable (MSS), and the remainder were classed as MSI-low (MSI-L).11

Immunostaining for the mismatch repair (MMR) proteins MLH1 and MSH2 was undertaken as described previously.12 If either MLH1 or MSH2 demonstrated lack of staining, the tumor was considered to be MMR deficient. Tumors possessing staining for both MLH1 and MSH2 were considered to be MMR intact.11

Among the 1087 patients included in this analysis, 125 were classified as having MSI-H tumors, 614 had MSI-L or MSS tumors, and 348 did not have blocks available for genotyping analysis. Furthermore, 87 patients were classified as having tumors with deficient staining for the MMR proteins, 580 had tumors with intact MMR staining, and 420 did not have blocks available for immunohistochemical analysis. In multivariate analyses, MSI status and staining for DNA MMR proteins were coded using an indicator variable to reflect missing data.

Study End Points

For this study, the primary end point was disease-free survival (DFS), defined as time from study enrollment to tumor recurrence, occurrence of a new primary colon cancer, or death as a result of any cause. In addition, recurrence-free survival (RFS) was defined as the time from study enrollment to tumor recurrence, death with evidence of recurrence, or occurrence of a new primary colon tumor. For RFS, patients who died without known tumor recurrence were censored at the last documented evaluation by the treatment provider. Finally, overall survival was defined as the time from study enrollment to death as a result of any cause.

Statistical Methods

All 3 end points (DFS, RFS, and overall survival) were examined using Kaplan-Meier curves and the log-rank test.13 Cox proportional hazards regression was used to determine the simultaneous impact of potential confounders.14 The proportionality of hazards assumption for the effect of family history was tested by examining it as a time-dependent covariate in the Cox model. The time-dependent family history covariate was not statistically significant (P = .95), indicating that the assumption of proportional hazards was appropriate. Covariates with missing variables were coded with indicator variables in adjusted models. We tested for linear trend by entering the number of relatives (0, 1, 2 or more) affected with colorectal cancer as a continuous variable into the multivariate model. Tests of interactions between family history of colorectal cancer and potentially modifying covariates, including treatment, were assessed by entering the cross product of family history and the covariate of interest.

Statistical significance was considered at the .05 level. We used SAS version 9.1 (SAS Inc, Cary, North Carolina) for all statistical analyses. Patient registration, clinical data collection, and statistical analyses were conducted by the CALGB Statistical Center, and all analyses were based on the study database frozen on March 2, 2007. Median follow-up time was calculated among surviving patients from the time of enrollment to the time at which the study database was frozen. Using the Clark C,15 the completeness of follow-up for this study was 83.25%. Applying the Wu modification16 to adjust for unreported deaths, a more realistic assessment of the completeness of follow-up was 85.0%.

Results for the clinical trial have been previously reported. No significant differences were found between the study treatment arms in either overall survival or DFS.8

Baseline characteristics for the 1087 patients for whom data on family history were captured are presented in Table 1. Among these 1087 participants, 195 (17.9%) reported a family history of colorectal cancer in 1 or more first-degree relatives. Compared with patients without a family history, those with a family history were less likely to have presented with clinical bowel obstruction (P = .02). Other potentially prognostic patient and tumor characteristics did not differ significantly according to family history.

Table Graphic Jump LocationTable 1. Baseline Characteristics by Family History of Colorectal Cancer

The median follow-up time from enrollment was 5.6 years (10th and 90th percentiles were 3.3 and 6.4 years, respectively). The predefined primary end point of this analysis was DFS (time to cancer recurrence or death as a result of any cause). A family history of colorectal cancer was associated with a significant reduction in the risk of cancer recurrence or mortality (Figure 2). This relationship remained largely unchanged after adjusting for other predictors of cancer recurrence (Table 2). Compared with patients without a family history, those with a family history had a multivariate hazard ratio (HR) of 0.72 (95% confidence interval [CI], 0.54-0.96) for cancer recurrence or death. Cancer recurrence or death occurred in 57 of 195 patients (29%; 95% CI, 23%-36%) with a family history of colorectal cancer compared with 343 of 892 patients (38%; 95% CI, 35%-42%) without a family history.

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Figure 2. Disease-Free Survival According to Family History of Colorectal Cancer
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Table Graphic Jump LocationTable 2. Unadjusted and Multivariate Adjusted Hazard Ratios for Recurrence-Free Survival, Disease-Free Survival, and Overall Survival According to Presence of Family Member With Colorectal Cancer

To isolate the influence of family history on cancer recurrences, we used the end point of RFS in secondary analyses. Compared with patients without a family history of colorectal cancer, those with a family history had a multivariate HR of 0.74 (95% CI, 0.55-0.99) for cancer recurrence (Table 2). Cancer recurrence occurred in 52 of 195 patients (27%; 95% CI, 21%-33%) with a family history of colorectal cancer and 316 of 892 patients (35%; 95% CI, 32%-39%) without a family history. Moreover, the adjusted HR for overall mortality among patients with a family history compared with patients without a family history was 0.75 (95% CI, 0.54-1.05). Death occurred in 43 of 195 patients (22%; 95% CI, 17%-28%) with a family history of colorectal cancer and 247 of 892 patients (28%; 95% CI, 25%-31%) without a family history.

The apparent benefit associated with family history was stronger with an increasing number of affected family members (Figure 3 and Table 3). Although the vast majority of patients with a family history reported 1 affected relative, there was a significant trend for improvement in DFS with an increasing number of affected family members. Compared with participants without a family history of colorectal cancer, those with 1 affected relative had a multivariate HR of 0.77 (95% CI, 0.57-1.04) for cancer recurrence or death. For participants with 2 or more affected relatives, we observed a greater reduction in risk (multivariate HR, 0.49; 95% CI, 0.23-1.04; P for trend with increasing number of affected relatives = .01). Cancer recurrence or death occurred in 50 of 165 patients (30%; 95% CI, 24%-38%) with 1 affected relative, 7 of 30 patients (23%; 95% CI, 12%-41%) with 2 or more affected relatives, and 343 of 892 patients (38%; 95% CI, 35%-42%) without a family history. We observed similar trends for cancer recurrence (RFS; P for trend = .03) and overall mortality (P for trend = .09) (Table 3).

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Figure 3. Disease-Free Survival According to Number of Family Members With History of Colorectal Cancer
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Table Graphic Jump LocationTable 3. Unadjusted and Multivariate Adjusted Hazard Ratios for Disease-Free Survival and Overall Survival According to Number of Family Members With Colorectal Cancer

We also examined whether the effect of family history varied according to the age at which the first-degree relative was diagnosed with colorectal cancer. Among patients whose relative was diagnosed with colorectal cancer at an age younger than 50 years, the adjusted HR for cancer recurrence or mortality (DFS) was 0.68 (95% CI, 0.36-1.29) compared with patients without a family history of colorectal cancer. For patients with a family member diagnosed with colorectal cancer at age 50 years or older, the adjusted HR for cancer recurrence or mortality was 0.73 (95% CI, 0.53-1.00). Cancer recurrence or death occurred in 10 of 36 patients (28%; 95% CI, 16%-44%) and 46 of 155 patients (30%; 95% CI, 23%-37%) with a history of colorectal cancer diagnosed in a family member at an age younger than 50 years and at 50 years or older, respectively.

We considered the possibility that patients with a family history of colorectal cancer might have a different prognosis related to earlier detection of their cancers. Although adjusting for depth of invasion (T stage) and nodal status (N stage) and the presence of clinical obstruction or perforation would minimize such biases, we further addressed this concern by repeating our analyses after excluding patients with earlier stage T1 and T2 tumors. However, restricting the analysis to patients with T3 and T4 tumors did not materially alter our results. Compared with patients without a family history, those with 1 or more affected first-degree relatives experienced a multivariate HR for cancer recurrence or death of 0.69 (95% CI, 0.51-0.94). Among patients with T3 and T4 tumors, cancer recurrence or death occurred in 49 of 165 patients (30%; 95% CI, 23%-37%) with a family history of colorectal cancer and 310 of 753 patients (41%; 95% CI, 38%-45%) without a family history.

We also repeated our analyses after excluding patients with a cancer detected in less than 4 positive lymph nodes (N1). Among patients with N2 disease (≥4 positive lymph nodes), our results remained largely unchanged: the adjusted HR for cancer recurrence or death among patients with a family history of colorectal cancer was 0.76 (95% CI, 0.49-1.17). Cancer recurrence or death occurred in 26 of 66 patients (39%; 95% CI, 29%-51%) with a family history of colorectal cancer and 156 of 321 patients (49%; 95% CI, 43%-54%) without a family history.

We also assessed the association between family history and DFS across strata of other potential predictors of patient outcome (Figure 4). The effect of family history on the risk of cancer recurrence or mortality was not significantly modified by baseline performance status, number of positive lymph nodes, or treatment arm. In contrast, the effect of family history appeared to differ according to patient age and sex. Among patients younger than 50 years, a family history of colorectal cancer was associated with an adjusted HR for cancer recurrence or death of 1.19 (95% CI, 0.61-2.31); among patients 50 years or older, the adjusted HR for family history was 0.66 (95% CI, 0.48-0.91). For patients younger than 50 years, cancer recurrence or death occurred in 14 of 40 patients (35%; 95% CI, 22%-50%) and 61 of 172 patients (35%; 95% CI, 29%-43%) with and without a family history, respectively. For patients 50 years or older, cancer recurrence or death occurred in 43 of 155 patients (28%; 95% CI, 21%-35%) and 282 of 720 patients (39%; 95% CI, 36%-43%) with and without a family history, respectively.

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Figure 4. Stratified Analysis of Disease-Free Survival (Comparison of Patients With a Family History of Colorectal Cancer With Those Without a Family History)
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A performance status of 0 indicates the patient was fully active; 1, restricted in physically strenuous activity but ambulatory and able to carry out light work; and 2, ambulatory and capable of all self-care but unable to carry out any work activities and up and about more than 50% of waking hours.

Among male patients, a family history of colorectal cancer was associated with an adjusted HR for cancer recurrence or death of 0.63 (95% CI, 0.44-0.91); among female patients, the adjusted HR for family history was 1.03 (95% CI, 0.64-1.63). For male patients, cancer recurrence or death occurred in 35 of 119 patients (29%; 95% CI, 22%-38%) and 202 of 488 patients (41%; 95% CI, 37%-46%) with and without a family history, respectively. For female patients, cancer recurrence or death occurred in 22 of 76 patients (29%; 95% CI, 20%-40%) and 141 of 404 patients (35%; 95% CI, 30%-40%) with and without a family history, respectively. Nonetheless, tests for interaction between patient age and the presence of a family history and patient sex and the presence of a family history did not reach statistical significance (P = .18 and P = .19, respectively). In addition, the effect of family history appeared stronger when the primary tumor was located in the right colon (cecum to splenic flexure) relative to the left colon (splenic flexure to the rectosigmoid junction). Among patients with tumors located in the right colon, the adjusted HR for DFS in patients with a family history was 0.61 (95% CI, 0.41-0.90) compared with those without a family history of colorectal cancer. Among patients with tumors located in the left colon, the adjusted HR for DFS was 1.01 (95% CI, 0.65-1.56). For patients with right-sided tumors, cancer recurrence or death occurred in 32 of 115 patients (28%; 95% CI, 20%-37%) and 195 of 486 patients (40%; 95% CI, 36%-45%) with and without a family history, respectively. For patients with left-sided tumors, cancer recurrence or death occurred in 25 of 75 patients (33%; 95% CI, 24%-45%) and 138 of 385 patients (36%; 95% CI, 31%-41%) with and without a family history, respectively. Nonetheless, a test of interaction between the site of the primary tumor and the presence of a family history did not reach statistical significance (P = .16).

We also examined whether family history modified the effect of adjuvant chemotherapy assignment on DFS. Among patients with a family history of colorectal cancer, those randomized to receive irinotecan, fluorouracil, and leucovorin had an adjusted HR for cancer recurrence or death of 1.07 (95% CI, 0.60-1.92) when compared with those who received fluorouracil and leucovorin. Similarly, among patients without a family history of colorectal cancer, the adjusted HR of death or recurrence for patients treated with irinotecan, fluorouracil, and leucovorin was 1.02 (95% CI, 0.83-1.27) compared with those who received fluorouracil and leucovorin. For patients with a family history of colorectal cancer, cancer recurrence or death occurred in 27 of 93 patients (29%; 95% CI, 21%-39%) randomized to receive irinotecan, fluorouracil, and leucovorin and 30 of 102 patients (29%; 95% CI, 21%-39%) randomized to receive fluorouracil and leucovorin. For patients without a family history of colorectal cancer, cancer recurrence or death occurred in 177 of 446 patients (40%; 95% CI, 35%-44%) randomized to receive irinotecan, fluorouracil, and leucovorin and 166 of 446 patients (37%; 95% CI, 33%-42%) randomized to receive fluorouracil and leucovorin.

Finally, we considered the possibility that the association between family history and improvement in DFS might be related to MSI status. Information regarding MSI status, as determined by genotyping, was available for 739 patients; information regarding immunostaining for the DNA MMR proteins MLH1 and MSH2 was available for 667 patients. The prevalence of MSI-H tumors was 24% (30/125; 95% CI, 17%-32%) and 15% (95/614; 95% CI, 13%-19%) among patients with and without a family history of colorectal cancer, respectively. The prevalence of tumors with deficient staining for MMR proteins was 21% (24/115; 95% CI, 14%-29%) and 11% (63/552; 95% CI, 9%-14%) among patients with and without a family history of colorectal cancer, respectively. Results remained largely unchanged after adjustment for MSI status: the adjusted HR for DFS was 0.73 (95% CI, 0.55-0.97) among patients with a family history of colorectal cancer compared with those without a family history. Similarly, the adjusted HR for DFS was 0.73 (95% CI, 0.55-0.97) among patients with a family history of colorectal cancer compared with those without a family history after adjusting for MMR status. Furthermore, the effect of family history on DFS did not appear to be modified by either MSI or MMR status (P for interaction = .51 and .45, respectively).

In a cohort of patients with stage III colon cancer treated with surgery and adjuvant chemotherapy, a history of colorectal cancer in a first-degree relative was associated with a significant reduction in cancer recurrence and mortality. Moreover, the apparent benefit associated with family history increased significantly with an increasing number of affected first-degree relatives, and the effect of family history appeared to be independent of tumoral MSI or DNA MMR status.

Numerous studies have demonstrated that family history of colorectal cancer increases the risk of developing colorectal cancer.25 However, few studies have examined the influence of family history of colorectal cancer on subsequent outcomes in patients with established cancer. Our findings are consistent with reports from a large registry of Japanese patients, which demonstrated improved 5-year survival among patients with colorectal cancer with a family history of the disease.7 In contrast, Slattery and Kerber6 found no overall effect of family history on survival of patients with colon cancer. However, the latter study was based on patients identified through a Utah cancer registry and had limited information on treatment, follow-up care, disease stage, and other prognostic factors.

Our study has several strengths because it is based on patients enrolled in an NCI-sponsored clinical trial. First, all patients had lymph node–positive cancer, reducing the impact of heterogeneity by disease stage. Second, treatment and follow-up care were standardized, and the date and nature of recurrence were recorded prospectively. Finally, extensive and detailed information on other prognostic factors was routinely collected.

Several limitations of this study deserve comment. First, because we relied on self-reported family history, misclassification of family history status may be possible. However, prior studies have demonstrated such data to be reliable.17 Moreover, because the data on family history were collected at study baseline before cancer recurrence, any errors in recall would have attenuated rather than exaggerated a true association with patient outcome.

Additionally, we did not collect information regarding number of siblings, and the likelihood of having a family history of the disease may vary according to the number of siblings at risk for the disease. However, it is unlikely that family size independently affects survival. Moreover, less detailed information of kindred size is likely nondifferential and would only bias our results toward finding no association between family history and survival.

Our analysis sought to assess the influence of family history beyond the rare, well-characterized hereditary colorectal cancer syndromes of familial adenomatous polyposis (FAP) or hereditary nonpolyposis colorectal cancer (HNPCC). Beyond obtaining data on colorectal cancer in first-degree family members, our trial did not specifically elicit information about the presence of FAP or HNPCC; nonetheless, fewer than 5% of colorectal cancer cases are attributable to these syndromes. Numerous studies demonstrate that a common (ie, nonsyndromic) family history of colorectal cancer significantly increases the risk of developing colorectal cancer, and the current analysis suggests that the presence of a common (ie, nonsyndromic) family history is significantly associated with an improved cancer survival. Although we cannot exclude the possibility that patients with multiple affected relatives in our trial may have included some patients with FAP or HNPCC, the vast majority of patients reporting a family history of colorectal cancer in this study were likely to have an undefined or sporadic familial predisposition toward developing colorectal cancer. Moreover, even among patients with only 1 affected relative, we observed a 25% reduction in cancer-specific and overall mortality.

We cannot completely exclude the possibility that patients with a family history may experience an improved prognosis due to earlier detection of malignancy. However, the effect of family history persisted after adjusting for other patient and disease characteristics associated with cancer recurrence or survival. Additionally, because patients were entered into a clinical trial that was restricted to stage III cancer, pathologic stage, administration of adjuvant therapy, and follow-up care were reasonably uniform among all participants. Moreover, the benefit associated with family history remained largely unchanged across the number of positive lymph nodes as well as baseline performance status. Although the effect of family history appeared to be modified by patient age, sex, and tumor location, tests for interaction were not significant, possibly because of limited statistical power. Further investigation to explore the relationship between family history and these factors is required.

Finally, because our study was based on a well-defined cohort enrolled in a clinical trial, our results may not be generalizable to a larger population of patients with colon cancer. However, the rate of family history in this cohort is similar to the general population of patients with colon cancer, and there is no evidence that family history appreciably varies according to participation in a clinical trial.

Studies suggest the importance of genetic contributions to the development of familial colorectal cancers.1820 However, the relationship between family history and outcome is likely to be complex and may be influenced by a confluence of genetic and environmental factors. We considered whether shared environmental or lifestyle factors might contribute to our findings but found no significant difference in smoking, median household income, body mass index, diet, and physical activity patterns between patients with and without a family history of colorectal cancer (Table 1).

Beyond rare, well-characterized hereditary colorectal cancer syndromes (eg, FAP or HNPCC), our data support the hypothesis that a relatively common though less penetrant genetic predisposition may not only influence colorectal cancer risk but also patient survival. This finding may reflect a distinct underlying molecular and pathogenic mechanism in cancers that develop in the setting of a common (ie, sporadic) family history. For example, data suggest that family history of colorectal cancer is associated with tumors with a higher frequency of microsatellite instability (MSI-H),21,22 which may be associated with improved prognosis compared with microsatellite stable tumors.2327 Consistent with the observation that MSI-H tumors are more common in the right colon,11,28 the beneficial effect of family history in the current study appeared greater among patients with right-sided colon cancer. However, our results remained largely unchanged after adjustment for MSI or MMR status, and we found no significant interaction between family history and MSI or MMR status. This suggests that the association between a sporadic (ie, nonsyndromic) family history and reduction in risk of cancer recurrence or death may be independent of MSI or MMR status. Nonetheless, family history may influence cancer prognosis through other pathways. Further studies are needed to more fully elucidate potential mechanisms by which a common family history may influence the outcome for patients with colorectal cancer.

Corresponding Author: Jennifer A. Chan, MD, MPH, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115 (jang@partners.org).

Author Contributions: Dr Chan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Chan, Saltz, Mayer, Bertagnolli, Fuchs.

Acquisition of data: Chan, Meyerhardt, Niedzwiecki, Hollis, Thomas, Schaefer, Whittom, Hantel, Bertagnolli, Fuchs.

Analysis and interpretation of data: Chan, Meyerhardt, Niedzwiecki, Hollis, Saltz, Goldberg, Warren, Bertagnolli, Fuchs.

Drafting of the manuscript: Chan, Bertagnolli, Fuchs.

Critical revision of the manuscript for important intellectual content: Chan, Meyerhardt, Niedzwiecki, Hollis, Saltz, Mayer, Thomas, Schaefer, Whittom, Hantel, Goldberg, Warren, Bertagnolli, Fuchs.

Statistical analysis: Chan, Meyerhardt, Hollis, Fuchs.

Obtained funding: Chan, Mayer, Schaefer, Warren, Fuchs.

Administrative, technical, or material support: Hollis, Saltz, Mayer, Thomas, Whittom, Goldberg, Warren, Bertagnolli, Fuchs.

Study supervision: Niedzwiecki, Goldberg, Fuchs.

Financial Disclosures: None reported.

Funding/Support: Cancer and Leukemia Group B (CALGB) 89803 was supported in part by grant CA31946 from the National Cancer Institute to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, chairman) and grant CA33601 to the CALGB Statistical Center (Stephen George, PhD) as well as support from Pharmacia & Upjohn Company, now Pfizer Oncology. Dr Chan is supported in part by grant T32-CA009001 from the National Cancer Institute. Drs Chan, Meyerhardt, Mayer, and Fuchs are supported by grants CA32291 and CA118553. Dr Niedzwiecki and Ms Hollis are supported by grants CA33601 and CA118553. Dr Saltz is supported by grant CA77651. Dr Thomas (Eastern Cooperative Oncology Group) is supported by grants CA21076, CA23318, CA66636, and CA21115. Dr Schaefer (North Central Cancer Treatment Group) is supported by grant CA35415. Dr Whittom (National Cancer Institute of Canada) is supported by grant CO15. Dr Hantel (Southwest Oncology Group) is supported by grants CA38926, CA32102, and CA46282. Dr Goldberg is supported by grant CA47559. Dr Warren is supported by grant CA60138. Dr Bertagnolli is supported by grant CA32291.

Role of the Sponsor: The sponsors had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Clinical Centers: Baptist Cancer Institute Community Clinical Oncology Program [CCOP], Memphis, Tennessee (Lee S. Schwartzberg, MD; supported by CA71323); Christiana Care Health Services Inc CCOP, Wilmington, Delaware (Stephen Grubbs, MD; supported by CA45418); University of North Carolina, Chapel Hill (Thomas C. Shea, MD; supported by CA47559); University of Chicago, Chicago, Illinois (Gini Fleming, MD; supported by CA41287); Dartmouth Medical School–Norris Cotton Cancer Center, Lebanon, New Hampshire (Marc S. Ernstoff, MD; supported by CA04326); Duke University Medical Center, Durham, North Carolina (Jeffrey Crawford, MD; supported by CA47577); Dana-Farber Cancer Institute, Boston, Massachusetts (Eric P. Winer, MD; supported by CA32291); Georgetown University Medical Center, Washington, DC (Edward Gelmann, MD; supported by CA77597); Cancer Centers of the Carolinas, Greenville, South Carolina (Jeffrey K. Giguere, MD; supported by CA29165); University of Illinois Minority-Based CCOP, Chicago (Lawrence E. Feldman, MD; supported by CA74811); University of Iowa, Iowa City (Gerald Clamon, MD; supported by CA47642); North Shore–Long Island Jewish Medical Center, Manhasset, New York (Daniel R. Budman, MD; supported by CA35279); University of Maryland Greenebaum Cancer Center, Baltimore (Martin Edelman, MD; supported by CA31983); University of Massachusetts Medical School, Worcester (William V. Walsh, MD; supported by CA37135); Massachusetts General Hospital, Boston (Michael L. Grossbard, MD; supported by CA12449); Mount Sinai Medical Center, Miami, Florida (Rogerio Lilenbaum, MD; supported by CA45564); University of Minnesota, Minneapolis (Bruce A. Peterson, MD; supported by CA16450); University of Missouri/Ellis Fischel Cancer Center, Columbia (Michael C. Perry, MD; supported by CA12046); Mount Sinai School of Medicine, New York, New York (Lewis R. Silverman, MD; supported by CA04457); Memorial Sloan-Kettering Cancer Center, New York (Clifford Hudis, MD; supported by CA77651); University of Nebraska Medical Center, Omaha (Anne Kessinger, MD; supported by CA77298); Long Island Jewish Medical Center, Lake Success, New York (Marc Citron, MD; supported by CA11028); The Ohio State University Medical Center, Columbus (Clara D. Bloomfield, MD; supported by CA77658); Rhode Island Hospital, Providence (William Sikov, MD; supported by CA08025); Roswell Park Cancer Institute, Buffalo, New York (Ellis Levine, MD; supported by CA02599); Southeast Cancer Control Consortium Inc CCOP, Goldsboro, North Carolina (James N. Atkins, MD; supported by CA45808); Southern Nevada Cancer Research Foundation CCOP, Las Vegas (John Ellerton, MD; supported by CA35421); Syracuse Hematology-Oncology Assoc CCOP, Syracuse, New York (Jeffrey Kirshner, MD; supported by CA45389); University of Tennessee at Memphis (Harvey B. Niell, MD; supported by CA47555); University of California at San Diego (Joanne Mortimer, MD; supported by CA11789); University of California at San Francisco (Alan P. Venook, MD; supported by CA60138); Vermont Cancer Center, Burlington (Hyman B. Muss, MD; supported by CA77406); Wake Forest University School of Medicine, Winston-Salem, North Carolina (David D. Hurd, MD; supported by CA03927); Walter Reed Army Medical Center, Washington, DC (Thomas Reid, MD; supported by CA26806); Washington University School of Medicine, St Louis, Missouri (Nancy Bartlett, MD; supported by CA77440); Weill Medical College of Cornell University, New York (Scott Wadler, MD; supported by CA07968).

Disclaimer: The contents of the manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

Lynch HT, de la Chapelle A. Hereditary colorectal cancer.  N Engl J Med. 2003;348(10):919-932
PubMed   |  Link to Article
Fuchs CS, Giovannucci EL, Colditz GA, Hunter DJ, Speizer FE, Willett WC. A prospective study of family history and the risk of colorectal cancer.  N Engl J Med. 1994;331(25):1669-1674
PubMed   |  Link to Article
Johns LE, Houlston RS. A systematic review and meta-analysis of familial colorectal cancer risk.  Am J Gastroenterol. 2001;96(10):2992-3003
PubMed   |  Link to Article
Potter JD, Slattery ML, Bostick RM, Gapstur SM. Colon cancer: a review of the epidemiology.  Epidemiol Rev. 1993;15(2):499-545
PubMed
Slattery ML, Kerber RA. Family history of cancer and colon cancer risk: the Utah Population Database.  J Natl Cancer Inst. 1994;86(21):1618-1626
PubMed   |  Link to Article
Slattery ML, Kerber RA. The impact of family history of colon cancer on survival after diagnosis with colon cancer.  Int J Epidemiol. 1995;24(5):888-896
PubMed   |  Link to Article
Registry Committee, Japanese Research Society for Cancer of the Colon and Rectum.  Clinical and pathological analyses of patients with a family history of colorectal cancer.  Jpn J Clin Oncol. 1993;23(6):342-349
PubMed
Saltz LB, Niedzwiecki D, Hollis D,  et al.  Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803.  J Clin Oncol. 2007;25(23):3456-3461
PubMed   |  Link to Article
Meyerhardt JA, Heseltine D, Niedzwiecki D,  et al.  Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803.  J Clin Oncol. 2006;24(22):3535-3541
PubMed   |  Link to Article
Meyerhardt JA, Niedzwiecki D, Hollis D,  et al.  Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer.  JAMA. 2007;298(7):754-764
PubMed   |  Link to Article
Bertagnolli MM, Compton CC, Niedzwiecki D,  et al.  Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, 5-fluorouracil and leucovorin in stage III colon cancer [abstract 10003 in 2006 ASCO Annual Meeting Proceedings].  J Clin Oncol. 2006; 24(18S):
Lindor NM, Burgart LJ, Leontovich O,  et al.  Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors.  J Clin Oncol. 2002;20(4):1043-1048
PubMed   |  Link to Article
Therneau T, Grambsch P. Modeling Survival Data. New York, NY: Springer; 2000
Jones MP, Crowley J. A general class of nonparametric tests for survival analysis.  Biometrics. 1989;45(1):157-170
PubMed   |  Link to Article
Clark TG, Altman DG, De Stavola BL. Quantification of the completeness of follow-up.  Lancet. 2002;359(9314):1309-1310
PubMed   |  Link to Article
Wu Y, Takkenberg JJ, Grunkemeier GL. Measuring follow-up completeness.  Ann Thorac Surg. 2008;85(4):1155-1157
PubMed   |  Link to Article
Kerber RA, Slattery ML. Comparison of self-reported and database-linked family history of cancer data in a case-control study.  Am J Epidemiol. 1997;146(3):244-248
PubMed   |  Link to Article
Cannon-Albright LA, Skolnick MH, Bishop DT, Lee RG, Burt RW. Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers.  N Engl J Med. 1988;319(9):533-537
PubMed   |  Link to Article
Cannon-Albright LA, Thomas TC, Bishop DT, Skolnick MH, Burt RW. Characteristics of familial colon cancer in a large population data base.  Cancer. 1989;64(9):1971-1975
PubMed   |  Link to Article
Rustgi AK. The genetics of hereditary colon cancer.  Genes Dev. 2007;21(20):2525-2538
PubMed   |  Link to Article
Ogino S, Kirkner G, Cantor M,  et al.  Family history of sporadic colorectal cancer modifies risks for specific molecular pathology in tumors: data from a prospective cohort of 86,220 women.  Mod Pathol. 2005;18:114A
Ricciardiello L, Goel A, Mantovani V,  et al.  Frequent loss of hMLH1 by promoter hypermethylation leads to microsatellite instability in adenomatous polyps of patients with a single first-degree member affected by colon cancer.  Cancer Res. 2003;63(4):787-792
PubMed
Gryfe R, Kim H, Hsieh ET,  et al.  Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer.  N Engl J Med. 2000;342(2):69-77
PubMed   |  Link to Article
Parc Y, Gueroult S, Mourra N,  et al.  Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer.  Gut. 2004;53(3):371-375
PubMed   |  Link to Article
Samowitz WS, Curtin K, Ma KN,  et al.  Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level.  Cancer Epidemiol Biomarkers Prev. 2001;10(9):917-923
PubMed
Benatti P, Gafa R, Barana D,  et al.  Microsatellite instability and colorectal cancer prognosis.  Clin Cancer Res. 2005;11(23):8332-8340
PubMed   |  Link to Article
Sinicrope FA, Rego RL, Halling KC,  et al.  Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients.  Gastroenterology. 2006;131(3):729-737
PubMed   |  Link to Article
Sinicrope FA, Rego RL, Foster N,  et al.  Microsatellite instability accounts for tumor site-related differences in clinicopathologic variables and prognosis in human colon cancers.  Am J Gastroenterol. 2006;101(12):2818-2825
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Derivation of Cohort Size
Graphic Jump Location

CALGB indicates Cancer and Leukemia Group B.

Place holder to copy figure label and caption
Figure 2. Disease-Free Survival According to Family History of Colorectal Cancer
Graphic Jump Location
Place holder to copy figure label and caption
Figure 3. Disease-Free Survival According to Number of Family Members With History of Colorectal Cancer
Graphic Jump Location
Place holder to copy figure label and caption
Figure 4. Stratified Analysis of Disease-Free Survival (Comparison of Patients With a Family History of Colorectal Cancer With Those Without a Family History)
Graphic Jump Location

A performance status of 0 indicates the patient was fully active; 1, restricted in physically strenuous activity but ambulatory and able to carry out light work; and 2, ambulatory and capable of all self-care but unable to carry out any work activities and up and about more than 50% of waking hours.

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics by Family History of Colorectal Cancer
Table Graphic Jump LocationTable 2. Unadjusted and Multivariate Adjusted Hazard Ratios for Recurrence-Free Survival, Disease-Free Survival, and Overall Survival According to Presence of Family Member With Colorectal Cancer
Table Graphic Jump LocationTable 3. Unadjusted and Multivariate Adjusted Hazard Ratios for Disease-Free Survival and Overall Survival According to Number of Family Members With Colorectal Cancer

References

Lynch HT, de la Chapelle A. Hereditary colorectal cancer.  N Engl J Med. 2003;348(10):919-932
PubMed   |  Link to Article
Fuchs CS, Giovannucci EL, Colditz GA, Hunter DJ, Speizer FE, Willett WC. A prospective study of family history and the risk of colorectal cancer.  N Engl J Med. 1994;331(25):1669-1674
PubMed   |  Link to Article
Johns LE, Houlston RS. A systematic review and meta-analysis of familial colorectal cancer risk.  Am J Gastroenterol. 2001;96(10):2992-3003
PubMed   |  Link to Article
Potter JD, Slattery ML, Bostick RM, Gapstur SM. Colon cancer: a review of the epidemiology.  Epidemiol Rev. 1993;15(2):499-545
PubMed
Slattery ML, Kerber RA. Family history of cancer and colon cancer risk: the Utah Population Database.  J Natl Cancer Inst. 1994;86(21):1618-1626
PubMed   |  Link to Article
Slattery ML, Kerber RA. The impact of family history of colon cancer on survival after diagnosis with colon cancer.  Int J Epidemiol. 1995;24(5):888-896
PubMed   |  Link to Article
Registry Committee, Japanese Research Society for Cancer of the Colon and Rectum.  Clinical and pathological analyses of patients with a family history of colorectal cancer.  Jpn J Clin Oncol. 1993;23(6):342-349
PubMed
Saltz LB, Niedzwiecki D, Hollis D,  et al.  Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803.  J Clin Oncol. 2007;25(23):3456-3461
PubMed   |  Link to Article
Meyerhardt JA, Heseltine D, Niedzwiecki D,  et al.  Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803.  J Clin Oncol. 2006;24(22):3535-3541
PubMed   |  Link to Article
Meyerhardt JA, Niedzwiecki D, Hollis D,  et al.  Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer.  JAMA. 2007;298(7):754-764
PubMed   |  Link to Article
Bertagnolli MM, Compton CC, Niedzwiecki D,  et al.  Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, 5-fluorouracil and leucovorin in stage III colon cancer [abstract 10003 in 2006 ASCO Annual Meeting Proceedings].  J Clin Oncol. 2006; 24(18S):
Lindor NM, Burgart LJ, Leontovich O,  et al.  Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors.  J Clin Oncol. 2002;20(4):1043-1048
PubMed   |  Link to Article
Therneau T, Grambsch P. Modeling Survival Data. New York, NY: Springer; 2000
Jones MP, Crowley J. A general class of nonparametric tests for survival analysis.  Biometrics. 1989;45(1):157-170
PubMed   |  Link to Article
Clark TG, Altman DG, De Stavola BL. Quantification of the completeness of follow-up.  Lancet. 2002;359(9314):1309-1310
PubMed   |  Link to Article
Wu Y, Takkenberg JJ, Grunkemeier GL. Measuring follow-up completeness.  Ann Thorac Surg. 2008;85(4):1155-1157
PubMed   |  Link to Article
Kerber RA, Slattery ML. Comparison of self-reported and database-linked family history of cancer data in a case-control study.  Am J Epidemiol. 1997;146(3):244-248
PubMed   |  Link to Article
Cannon-Albright LA, Skolnick MH, Bishop DT, Lee RG, Burt RW. Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers.  N Engl J Med. 1988;319(9):533-537
PubMed   |  Link to Article
Cannon-Albright LA, Thomas TC, Bishop DT, Skolnick MH, Burt RW. Characteristics of familial colon cancer in a large population data base.  Cancer. 1989;64(9):1971-1975
PubMed   |  Link to Article
Rustgi AK. The genetics of hereditary colon cancer.  Genes Dev. 2007;21(20):2525-2538
PubMed   |  Link to Article
Ogino S, Kirkner G, Cantor M,  et al.  Family history of sporadic colorectal cancer modifies risks for specific molecular pathology in tumors: data from a prospective cohort of 86,220 women.  Mod Pathol. 2005;18:114A
Ricciardiello L, Goel A, Mantovani V,  et al.  Frequent loss of hMLH1 by promoter hypermethylation leads to microsatellite instability in adenomatous polyps of patients with a single first-degree member affected by colon cancer.  Cancer Res. 2003;63(4):787-792
PubMed
Gryfe R, Kim H, Hsieh ET,  et al.  Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer.  N Engl J Med. 2000;342(2):69-77
PubMed   |  Link to Article
Parc Y, Gueroult S, Mourra N,  et al.  Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer.  Gut. 2004;53(3):371-375
PubMed   |  Link to Article
Samowitz WS, Curtin K, Ma KN,  et al.  Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level.  Cancer Epidemiol Biomarkers Prev. 2001;10(9):917-923
PubMed
Benatti P, Gafa R, Barana D,  et al.  Microsatellite instability and colorectal cancer prognosis.  Clin Cancer Res. 2005;11(23):8332-8340
PubMed   |  Link to Article
Sinicrope FA, Rego RL, Halling KC,  et al.  Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients.  Gastroenterology. 2006;131(3):729-737
PubMed   |  Link to Article
Sinicrope FA, Rego RL, Foster N,  et al.  Microsatellite instability accounts for tumor site-related differences in clinicopathologic variables and prognosis in human colon cancers.  Am J Gastroenterol. 2006;101(12):2818-2825
PubMed   |  Link to Article

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