In Response: We appreciate the opportunity to respond to the concerns raised by Dr. Risch related to our recent publication about the relationship between cyclin E overexpression and epidemiologic risk factors in ovarian cancer (1). The first concern was with the statistical significance of the difference in the number of lifetime ovulatory cycles among the cyclin E–positive and cyclin E–negative ovarian cancer cases. Dr. Risch suggested that we use a 2-degree-of-freedom test to evaluate the significance of this relationship. The second concern related to the inclusion of mucinous cases, which Dr. Risch believes are not associated with reproductive risk factors such as ovulation and oral contraceptive use that predispose to other histologic types of ovarian cancer.

In response to these concerns, we provide Table 1 below, which shows the case-case analysis of lifetime ovulatory cycle tertiles previously reported in Table 4 of the article, but now without mucinous cases. We have also included the P values from the 2-degree-of-freedom test. Removing the 60 (7 cyclin E positive and 53 cyclin E negative) mucinous cases results in the point estimates becoming somewhat stronger, and the P values show strong statistical significance. Addressing the second concern, we repeated the analysis in Table 3 of our article omitting mucinous cancers, and the results were virtually identical to our original findings. These results are given in Table 2. The point estimate for the relationship between lifetime ovulatory cycles among cyclin E–positive cases compared with controls remained the same as in the original analysis [odds ratio, 1.18; 95% confidence interval (95% CI), 1.07–1.30], whereas the point estimate for the association between lifetime ovulatory cycles and the cyclin E–negative cases compared with controls changed slightly from 1.05 (95% CI, 0.98–1.14) to 1.06 (95% CI, 0.97-1.15). The odds ratios and 95% CIs for the relationship between the number of years pregnant and years of oral contraceptive use in the analysis of cyclin E–positive cases and cyclin E–negative cases compared with controls are also similar to the original analyses that included the mucinous cases.

Table 1.

Case-case analysis shown in Table 4 of original article but omitting mucinous cancers

No. of LOCsCyclin E+
Cyclin E−
OR* (95% CI)2-df P
nnAll cases
    <265 38 75 0.003 
    265-390 67 101 1.3 (0.8-2.4)  
    >390 101 76 2.6 (1.4-4.7)  
Premenopausal     
    <265 21 46 0.045 
    265-390 26 42 1.9 (0.8-4.5)  
    >390 19 17 4.5 (1.4-14.6)  
Postmenopausal     
    <265 17 29 0.024 
    265-390 41 59 1.1 (0.5-2.4)  
    >390 82 59 2.2 (1.0-4.6)  
No. of LOCsCyclin E+
Cyclin E−
OR* (95% CI)2-df P
nnAll cases
    <265 38 75 0.003 
    265-390 67 101 1.3 (0.8-2.4)  
    >390 101 76 2.6 (1.4-4.7)  
Premenopausal     
    <265 21 46 0.045 
    265-390 26 42 1.9 (0.8-4.5)  
    >390 19 17 4.5 (1.4-14.6)  
Postmenopausal     
    <265 17 29 0.024 
    265-390 41 59 1.1 (0.5-2.4)  
    >390 82 59 2.2 (1.0-4.6)  

Abbreviations: LOC, lifetime ovulatory cycle; df, degrees of freedom.

*

Adjusted for age at diagnosis/interview (cubic spline), race (Black or non-Black), body mass index (kg/m2; continuous), tubal ligation (yes/no), family history of breast or ovarian cancer in first-degree relative (yes/no), and infertility (yes/no), as well as stage (I or II versus III or IV) and grade (low malignant potential, 1/2, 3/4).

Table 2.

Case-control analyses derived from Table 3 of original article but omitting mucinous cancers

Cyclin E+ vs controls
Cyclin E− vs controls
OR* (95% CI)POR* (95% CI)P
Composite LOC 1.18 (1.07-1.30) 0.001 1.06 (0.97-1.15) 0.181 
Tubal ligation (yes or no) 0.62 (0.42-0.91) 0.015 0.56 (0.39-0.80) 0.001 
Family history of breast/ovarian cancer in first-degree relative (yes or no) 1.28 (0.92-1.78) 0.143 1.26 (0.91-1.73) 0.163 
BMI (kg/m21.02 (1.00-1.05) 0.099 1.02 (1.00-1.04) 0.127 
Infertility (yes or no) 1.86 (1.24-2.77) 0.003 1.48 (1.00-2.18) 0.049 
LOC component     
    Age at menarche (per year) 1.00 (0.89-1.12) 0.958 0.94 (0.85-1.04) 0.206 
    Age at last period (per year) 1.01 (0.97-1.06) 0.545 1.06 (1.02-1.11) 0.007 
    Breast-feeding exclusively (per year) 0.69 (0.40-1.21) 0.193 0.92 (0.61-1.39) 0.689 
    Pregnancy (per year) 0.80 (0.66-0.96) 0.018 0.91 (0.77-1.08) 0.290 
    Oral contraceptive use (per year) 0.91 (0.87-0.95) <0.0001 0.98 (0.95-1.01) 0.169 
    Irregular cycles (per year) 0.97 (0.94-1.00) 0.077 0.99 (0.96-1.02) 0.501 
    Missed periods (per 12 periods) 1.02 (1.00-1.04) 0.068 1.00 (0.97-1.02) 0.744 
    HRT duration (per year) 1.02 (0.99-1.05) 0.160 1.05 (1.02-1.07) 0.002 
    Tubal ligation (yes or no) 0.66 (0.43-1.01) 0.055 0.56 (0.39-0.82) 0.003 
    Family history of breast/ovarian cancer in first-degree relative (yes or no) 1.24 (0.88-1.74) 0.223 1.27 (0.91-1.75) 0.156 
    BMI (kg/m21.03 (1.00-1.05) 0.045 1.02 (1.00-1.05) 0.120 
    Infertility (yes or no) 1.71 (1.12-2.62) 0.013 1.48 (0.98-2.22) 0.061 
Cyclin E+ vs controls
Cyclin E− vs controls
OR* (95% CI)POR* (95% CI)P
Composite LOC 1.18 (1.07-1.30) 0.001 1.06 (0.97-1.15) 0.181 
Tubal ligation (yes or no) 0.62 (0.42-0.91) 0.015 0.56 (0.39-0.80) 0.001 
Family history of breast/ovarian cancer in first-degree relative (yes or no) 1.28 (0.92-1.78) 0.143 1.26 (0.91-1.73) 0.163 
BMI (kg/m21.02 (1.00-1.05) 0.099 1.02 (1.00-1.04) 0.127 
Infertility (yes or no) 1.86 (1.24-2.77) 0.003 1.48 (1.00-2.18) 0.049 
LOC component     
    Age at menarche (per year) 1.00 (0.89-1.12) 0.958 0.94 (0.85-1.04) 0.206 
    Age at last period (per year) 1.01 (0.97-1.06) 0.545 1.06 (1.02-1.11) 0.007 
    Breast-feeding exclusively (per year) 0.69 (0.40-1.21) 0.193 0.92 (0.61-1.39) 0.689 
    Pregnancy (per year) 0.80 (0.66-0.96) 0.018 0.91 (0.77-1.08) 0.290 
    Oral contraceptive use (per year) 0.91 (0.87-0.95) <0.0001 0.98 (0.95-1.01) 0.169 
    Irregular cycles (per year) 0.97 (0.94-1.00) 0.077 0.99 (0.96-1.02) 0.501 
    Missed periods (per 12 periods) 1.02 (1.00-1.04) 0.068 1.00 (0.97-1.02) 0.744 
    HRT duration (per year) 1.02 (0.99-1.05) 0.160 1.05 (1.02-1.07) 0.002 
    Tubal ligation (yes or no) 0.66 (0.43-1.01) 0.055 0.56 (0.39-0.82) 0.003 
    Family history of breast/ovarian cancer in first-degree relative (yes or no) 1.24 (0.88-1.74) 0.223 1.27 (0.91-1.75) 0.156 
    BMI (kg/m21.03 (1.00-1.05) 0.045 1.02 (1.00-1.05) 0.120 
    Infertility (yes or no) 1.71 (1.12-2.62) 0.013 1.48 (0.98-2.22) 0.061 

Abbreviations: BMI, body mass index; HRT, hormone replacement therapy.

*

Adjusted for age at diagnosis/interview (cubic spline), race (Black or non-Black), body mass index (kg/m2; continuous), tubal ligation (yes or no), family history of breast or ovarian cancer in first-degree relative (yes or no), and infertility (yes or no).

We also want to point out that the P value of 0.11 derived by Dr. Risch for the relationship between oral contraceptive use and cyclin E–positive and cyclin E–negative cases clearly cannot be correct because the 95% confidence limits do not even overlap (Table 3). We do not know how Dr. Risch came up with what he calls a “rough estimate” P value, but when we conducted a case-only analysis of this relationship we found a P value of 0.0004. In a similar analysis of the number of lifetime ovulatory cycles in positive cases compared with negative cases, we calculated a P value of 0.003. In doing this reanalysis, we noticed that in the footnote to Table 3 we incorrectly reported that the sample size of cyclin E–negative cases was 166, when in fact the sample size is 299. This may explain the discrepancy between Dr. Risch's rough estimate P value being >0.05 and the fact that the confidence intervals do not overlap.

We appreciate Dr. Risch's thoughtful comments and the opportunity to provide further analyses, which address these issues.

No potential conflicts of interest were disclosed.

1
Schildkraut JM, Moorman PG, Bland AE, et al. Cyclin E overexpression in epithelial ovarian cancer characterizes an etiologic subgroup.
Cancer Epidemiol Biomarkers Prev
2008
;
17
:
585
–93.