The Effect of Body Mass Index and Weight Change on Epithelial Ovarian Cancer Survival in Younger Women: A Long-Term Follow-Up Study

Abstract

Objective:

The objective of this study was to assess the relationship between body mass index (BMI) and epithelial ovarian cancer survival among young women.

Methods:

We conducted a cohort analysis of 425 women aged 20–54 years with incident epithelial ovarian cancer enrolled during 1980–1982 in Cancer and Steroid Hormone (CASH), a population-based, case-control study. Participants' vital status was ascertained though linkage with the Surveillance, Epidemiology and End Results (SEER) program. Using Cox proportional hazards models, we estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the association between survival and usual adult BMI, BMI at age 18, and weight change from age 18 to adult.

Results:

During a follow-up of up to 17 years, 215 women died. Compared to women with an adult BMI in the lowest quartile (<20.7), women in the second (20.8–22.5), third (22.6–24.9), and fourth (≥25.0) quartiles were not at increased risk for death (HR 1.2, 95% CI 0.8-1.8; HR 1.1, 95% CI 0.7-1.6; and HR 0.9, 95% CI 0.6-1.4, respectively) (p trend=0.6). Similarly, neither age 18 BMI nor weight change were associated with ovarian cancer survival.

Conclusions:

Although elevated BMI is associated with increased ovarian cancer risk among young women, we found no evidence of its association with ovarian cancer survival in this population.

Introduction

Ovarian cancer is the leading cause of death from a gynecologic malignancy among women in the United States, with an estimated 14,600 deaths occurring in 2009.^1
–3 Most women are diagnosed with ovarian cancer at advanced stages when the prognosis is poor.^4
–6 Furthermore, ovarian cancer tends to recur, even in patients who achieve remission after treatment with surgery and chemotherapy.⁷

Elevated body mass index (BMI) is reported to increase risk for some cancers in women, including such hormonally related cancers as breast and endometrial cancer,^8,9 as well as ovarian cancer, particularly in younger, premenopausal women.^10,11 Elevated BMI also is associated with an increased risk for death after diagnosis of breast and endometrial cancers.^12,13 The effect of BMI on prognosis after breast or endometrial cancer may be attributed to a number of factors, such as delayed detection¹⁴ or biologic influences of endogenous estrogen levels on tumor biology.¹⁵ Although elevated BMI is a poor prognostic factor for breast and endometrial cancers, its effect on ovarian cancer survival is less clear. Studies of the effect of elevated BMI on ovarian cancer survival show inconsistent results; some studies found an increased risk of death with increasing BMI,^15

–20 and others found no association.^{13,21

–25} Variation in study results may be related to the age of study participants, with a stronger effect noted in younger women, as seen in studies of ovarian cancer incidence.¹¹ Additionally, little is known about the effect of weight change over the life course on ovarian cancer survival.

We linked data from women aged 20–54 with incident epithelial ovarian cancer in the Cancer and Steroid Hormone (CASH) study with vital status data from the Surveillance, Epidemiology and End Results (SEER) program to examine the effects of usual adult BMI, BMI at age 18, and weight change from age 18 to adulthood on survival after diagnosis. An earlier analysis of a smaller subset of CASH epithelial ovarian cancer cases found no relationship between adult BMI≥27.9 and 5-year survival after diagnosis.²⁵ We seek to expand these analyses by examining additional categories of adult BMI in a larger sample as well as BMI at age 18 and weight change from age 18 to adulthood in a follow-up period that extends up to 17 years. We hypothesized that elevated BMI would be associated with increased risk of death among young women with epithelial ovarian cancer. Information from this study could be used to improve the accuracy of prognostic predictions in women with ovarian cancer. If there is an association between usual adult BMI, age 18 BMI, weight change or BMI category change and ovarian cancer survival, physicians can additionally examine BMI when determining a patient's prognosis.

Materials and Methods

The CASH study is a multicenter, population-based, case-control study designed to assess the relationship between oral contraceptive use and the risk of breast, endometrial, and ovarian cancers.²⁶ The study received approval through the Institutional Review Board at the Centers for Disease Control and Prevention (CDC). Methods have been described previously.²⁷ Briefly, ovarian cancer cases were women aged 20–54 years who were diagnosed with histologically confirmed primary ovarian cancer between December 1, 1980, and December 31, 1982. Cases were identified through SEER program registries in eight U.S. study areas (Atlanta, Detroit, San Francisco, Seattle, Connecticut, Iowa, New Mexico, and four urban counties of Utah). Of the 816 women fulfilling the case definition, 575 (70%) participated in the CASH study.²⁶ Only 5.2% of eligible women refused to participate. Other reasons for nonparticipation included inability to conduct an interview within 6 months of selection (12.7%), illness (5.1%), death (3.1%), and refusal by a physician (2.9%).

Trained interviewers administered an in-home questionnaire to ovarian cancer patients within 6 months of diagnosis. Information collected included reproductive history, use of contraception and hormonal medications, family and personal medical histories, and personal characteristics. Women were asked their current height, usual weight as an adult, and weight at age 18. BMI was calculated by dividing weight in kilograms by height in square meters.

Information on vital status through December 31, 1997, was ascertained by linking CASH interview data from ovarian cancer cases with SEER public access data files.²⁸ We successfully linked 494 (86%) of the CASH ovarian cancer cases to their respective SEER record using the following match criteria: sex, cancer site, geographic location, SEER identification number, birth year, and date of diagnosis (within 2 months). Survival time was defined as the time from diagnosis to either the date of death or the date last known to be alive. For analysis, we excluded ovarian cancer cases other than epithelial (n=41), with unknown type (n=5), missing or in situ stage (n=9 and n=1, respectively), tumors that were benign (n=2) or metastatic (n=8), and cases missing adult or age 18 weight (n=1 and n=2, respectively). After exclusions, 425 cases remained for analysis.

Our main exposures of interest were usual adult BMI, age 18 BMI, and weight change. We categorized adult and age 18 BMI using World Health Organization (WHO) definitions of normal (18.5–24.9), overweight (25.0–29.9), and obese (≥30.0) and additionally examined quartiles of usual adult BMI (≤20.7, 20.8–22.5, 22.6–24.9, and≥25.0) and age 18 BMI (≤18.8, 18.9–20.4, 20.5–22.3, ≥22.4). We categorized weight change as weight gain in pounds (<0, 0–10, 11–20, 21–30, ≥31), as well as BMI category change from age 18 to adult using the following four categories based on WHO classifications: (1) normal BMI at age 18 and as an adult (no change), (2) normal BMI at age 18 and overweight/obese as an adult, (3) overweight/obese at age 18 and normal BMI as an adult, and (4) overweight/obese at age 18 and as an adult (no change).

Kaplan-Meier curves were used to compare survival by BMI and weight change category, and differences were tested with the log-rank test. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) of the associations between usual adult BMI, age 18 BMI, weight change, and BMI category change with ovarian cancer survival. We examined ovarian cancer-specific mortality (ICD-9 codes 183.0–183.9) as well as all-cause mortality.

Models were adjusted for a set of confounders, selected a priori, on the basis of previous literature. These variables included age at diagnosis, SEER stage of disease, and histologic type of epithelial ovarian cancer. Histologic type in the CASH study was based on a review of cancer specimens by a panel of three pathologists. Specimen slides were available for 90% of the cases and were classified as mucinous, serous, endometriod, clear cell, and other. We examined other potential confounding variables, including reproductive factors (age at menarche, parity, menopausal status, oral contraceptive use, and estrogen replacement therapy use), demographic factors (race, income, and marital status), family history of breast or ovarian cancer, personal history of polycystic ovary disease or noncancerous ovarian cysts, primary treatment (surgery, radiation, or both), smoking status, and history of any chronic conditions (diabetes, high blood pressure, chronic kidney disease, gallbladder disease, myocardial infarction, heart disease, high cholesterol, paralysis, or stroke). Only oral contraceptive use, menopausal status, parity, smoking status, and presence of other chronic conditions were found to significantly alter point estimates and were, therefore, included in adjusted models.

Previous studies suggested that the relationship between BMI and ovarian cancer survival may be modified by some factors.^17,18 Therefore, we also examined whether our results varied by stage at diagnosis, age at diagnosis, menopausal status, histology, and smoking status. Effect modification was assessed using the log-likelihood test comparing the full model with the interaction term and the reduced model without the interaction term. Tests for trend were calculated using the p value associated with the Wald chi-square test for linear trend. The adequacy of Cox proportional hazards assumptions was checked with interaction terms between included variables and time. SAS version 9.2 was used to conduct all analyses.

Results

Among the 425 women diagnosed with epithelial ovarian cancer in the study population, 76 (17.9%) were overweight (usual adult BMI 25.0–29.9) and 28 (6.6%) were obese (usual adult BMI ≥30.0). Significant differences in the age at diagnosis and age at menarche and the presence of comorbid conditions were noted across quartiles of usual adult BMI (Table 1). Overweight/obese women (BMI≥25.0) were significantly more likely than women in quartiles 1–3 to be diagnosed after age of 40, have a younger age at menarche, and have comorbid chronic conditions.

Table 1.

Distribution of Select Characteristics by Quartiles of Usual Adult Body Mass Index Among Women with Primary Epithelial Ovarian Cancer

		Adult BMI (quartiles)
Characteristic	All n=425 (100%)	≤20.7 n=100 (23.5%)	20.8–22.5 n=107 (25.1%)	22.6–24.9 n=116 (27.3%)	≥25.0 n=102 (24.0%)
Age at diagnosis, years^a
20–40	31.5	43.0	31.8	27.6	24.5
41–50	43.1	45.0	29.3	39.7	49.0
51–54	25.4	12.0	29.0	32.8	26.5
Stage of disease
Localized	40.0	41.0	37.4	41.4	40.2
Regional/distant	60.0	59.0	62.6	58.6	59.8
Histology
Serous	46.4	43.0	54.2	41.4	47.1
Mucinous	13.4	14.0	13.1	13.8	14.7
Endometrioid	11.8	13.0	9.4	9.5	15.7
Other	28.0	30.0	23.4	35.3	22.6
Surgery	97.2	99.0	94.4	99.1	96.1
Radiation therapy	7.8	8.0	4.7	9.5	8.8
Race
White	92.0	91.0	92.5	94.8	89.2
Black	4.2	5.0	2.8	3.5	5.9
Other	3.8	4.0	4.7	1.7	4.9
Currently married	71.5	68.0	75.7	75.9	65.7
Family history of breast/ovarian cancer	12.0	8.0	11.2	14.7	13.7
Age at menarche^a
<12	19.1	13.0	17.8	14.7	31.4
12–13	55.1	53.0	57.0	63.8	45.1
≥14	24.9	34.0	23.4	20.7	22.6
Parity
Nulliparous	25.2	27.0	28.0	21.6	24.5
1–2	41.2	45.0	42.1	47.4	29.4
≥3	33.4	28.0	29.9	31.0	45.1
Menopausal status
Premenopausal/perimenopausal	63.3	72.0	67.3	56.0	58.8
Postmenopausal	32.0	21.0	30.8	38.8	36.3
Current smoker	38.8	46.0	40.2	35.3	34.3
Oral contraceptive use
Never	57.7	50.0	51.4	66.4	61.8
Ever	42.1	50.0	48.6	33.6	37.3
Estrogen replacement therapy use
Never	58.1	54.0	59.8	58.6	59.8
Ever	5.9	4.0	6.5	7.8	4.9
Other^b	36.0	42.0	33.6	33.6	35.3
History of polycystic ovary disease	3.3	6.0	1.9	5.2	0.0
History of noncancerous ovarian cysts	19.3	20.0	18.7	19.0	19.6
Presence of other chronic conditions^a,c	31.8	15.0	24.3	30.2	57.8

Because of missing information for some variables, not all column percents sum to 100.

p value<0.05, Pearson chi-square test.

Indicates women with unknown estrogen replacement therapy status, women who were premenopausal, or women who used estrogen replacement therapy before their last menstrual period.

Presence of any other chronic conditions, including diabetes, high blood pressure, chronic kidney disease, gallbladder disease, myocardial infarction, heart disease, high cholesterol, paralysis, or stroke.

During a median follow-up of 9.7 years, 215 women died, of whom 170 (79%) had ovarian cancer listed as the cause of death. Among the 45 nonovarian cancer deaths, 24 (53%) were coded as other or unknown neoplasms, 8 (18%) did not have a death certificate available, and the remaining causes of death were attributed to heart disease (n=5), cerebrovascular disease (n=2), circulatory disease (n=2), diabetes (n=1), and other unspecified causes (n=3). Because findings were similar for ovarian cancer-specific and all-cause mortality, results are shown only for all-cause mortality. Overall rates of 5-year, 10-year, and 15-year survival were 62% (95% CI 57-67%), 53% (95% CI 48-58%), and 49% (95% CI 44-54%), respectively (Table 2). Survival did not significantly differ by adult BMI, age 18 BMI, or weight change.

Table 2.

Kaplan-Meier Estimates of Survival from Any Cause of Death Among Women Diagnosed with Primary Epithelial Ovarian Cancer

			Survival probability (95% CI)
	n	Deaths	5 year	10 year	15 year	p value ^a
Overall	425	215	0.62 (0.57-0.67)	0.53 (0.48-0.58)	0.49 (0.44-0.54)
Usual adult BMI (kg/m²)
≤20.7	100	42	0.69 (0.60-0.78)	0.59 (0.49-0.69)	0.56 (0.46-0.66)	0.5
20.8–22.5	107	58	0.61 (0.59-0.63)	0.50 (0.41-0.59)	0.47 (0.38-0.56)
22.6–24.9	116	62	0.59 (0.50-0.68)	0.49 (0.40-0.58)	0.47 (0.38-0.57)
≥25.0	102	49	0.61 (0.52-0.70)	0.54 (0.44-0.64)	0.47 (0.37-0.57)
Age 18 BMI (kg/m²)
≤18.8	112	56	0.60 (0.51-0.69)	0.54 (0.45-0.63)	0.50 (0.41-0.59)	0.7
18.9–20.4	101	46	0.71 (0.62-0.80)	0.58 (0.48-0.68)	0.54 (0.44-0.64)
20.5–22.3	113	58	0.58 (0.49-0.67)	0.51 (0.42-0.60)	0.48 (0.39-0.57)
≥22.4	99	55	0.61 (0.51-0.71)	0.49 (0.39-0.59)	0.45 (0.35-0.55)
Weight gain (lbs)
<0	50	25	0.69 (0.56-0.82)	0.55 (0.41-0.69)	0.50 (0.36-0.64)	0.6
0–10	167	79	0.60 (0.53-0.67)	0.53 (0.45-0.61)	0.52 (0.44-0.60)
11–20	92	46	0.65 (0.55-0.75)	0.55 (0.45-0.65)	0.50 (0.40-0.60)
21–30	53	27	0.68 (0.55-0.81)	0.55 (0.42-0.68)	0.51 (0.38-0.64)
≥31	63	38	0.55 (0.43-0.67)	0.46 (0.34-0.58)	0.37 (0.25-0.49)
BMI category change
Normal weight to normal weight	313	156	0.63 (0.58-0.68)	0.53 (0.47-0.59)	0.50 (0.44-0.55)	0.8
Normal weight to overweight/obese	79	43	0.59 (0.48-0.70)	0.52 (0.41-0.63)	0.45 (0.34-0.56)
Overweight/obese to normal weight	10	6	0.60 (0.30-0.90)	0.40 (0.10-0.70)	0.40 (0.10-0.70)
Overweight/obese to overweight/obese	23	10	0.65 (0.45-0.85)	0.60 (0.40-0.80)	0.56 (0.35-0.77)

p value calculated based on the log rank test.

BMI, body mass index; CI, confidence interval.

Compared to epithelial ovarian cancer cases with an adult BMI in the lowest quartile (<20.7), women with an adult BMI in the second (20.8–22.5), third (22.6–24.9), and fourth (≥25.0) quartiles were not at increased risk for death after adjustment for covariates (HR 1.2, 95% CI 0.81-1.82; HR 1.1, 95% CI 0.7-1.6; and HR 0.9, 95% CI 0.6-1.4, respectively) (p trend=0.6) (Table 3). Excluding underweight women with a BMI ≤18.5 did not significantly alter the findings. Using WHO categories of adult and age 18 BMI yielded similar results; compared to those with normal adult BMIs (18.5–24.9), overweight women (BMI 25.0–29.9) and obese women (BMI ≥30.0), were not at an increased risk for death (HR 0.9, 95% CI 0.6-1.3; HR 0.8, 95% CI 0.5-1.4, respectively) (Table 3).

Table 3.

Cox Proportional Hazards Models of Effect of Usual Adult Body Mass Index, Age 18 Body Mass Index, Weight Change, and Body Mass Index Category Change from Age 18 to Adult on Mortality Risk After Diagnosis with Primary Epithelial Ovarian Cancer

	n	Number of Deaths	Adjusted HR^a (95% CI)	p trend ^b
Usual Adult BMI (kg/m²)
≤20.7	100	42	Referent	0.6
20.8–22.5	107	58	1.21 (0.81-1.82)
22.6–24.9	116	62	1.05 (0.69-1.58)
≥25.0	102	53	0.92 (0.60-1.43)
Age 18 BMI (kg/m²)
≤18.8	112	56	Referent	0.5
18.9–20.4	101	46	1.04 (0.69-1.55)
20.5–22.3	113	58	1.30 (0.89-1.89)
≥22.4	99	55	1.21 (0.82-1.78)
Weight gain (lbs)
<0	50	25	Referent	0.1
0–10	167	79	1.22 (0.77-1.93)
11–20	92	46	0.83 (0.50-1.38)
21–30	53	27	0.71 (0.41-1.25)
≥31	63	38	0.84 (0.49-1.44)
BMI category change
Normal weight to normal weight	313	156	Referent	N/A
Normal weight to overweight/obese	79	43	0.88 (0.62-1.26)
Overweight/obese to normal weight	10	6	1.01 (0.44-2.32)
Overweight/obese to overweight/obese	23	10	0.74 (0.38-1.42)

Hazard ratio (HR) is adjusted for age at diagnosis, stage at diagnosis, histologic type, oral contraceptive use, parity, menopausal status, and presence of any other chronic conditions, including diabetes, high blood pressure, chronic kidney disease, gallbladder disease, myocardial infarction, heart disease, high cholesterol, paralysis, or stroke.

p value for trend calculated based on the Wald chi-square test.

N/A, not applicable.

Weight change was not associated with risk of death after adjustment for confounders (Table 3). Compared to women who lost weight, women with the most weight gain (≥31 pounds) were not at significantly increased risk of death (HR 0.8, 95% CI 0.5-1.4). Similarly, changes in BMI category from age 18 to adult were not associated with increased risk of death (Table 3). Dichotomizing adult and age 18 BMI at <25.0 vs. ≥25.0 and examining BMI as a continuous variable did not alter the findings. The results for adult BMI, BMI at age 18, and weight change did not vary by age at diagnosis, stage at diagnosis, menopausal status, histology, or smoking status (results not shown).

Discussion

In this cohort, survival among young women diagnosed with epithelial ovarian cancer was not independently associated with usual adult BMI, age 18 BMI, or change in weight or BMI category from age 18 to adult. Our results were consistent with those of other studies,^{13,20

–23,25,29
–31} including a large Swedish study that examined both adult and age 18 BMI and included multiple anthropometric and lifestyle factors²³ and another American study that examined adult BMI and included detailed examinations of treatment regimens.³¹ Although each of these studies was conducted in older women (>50 years of age), both found that overweight and obese women were not at significantly increased risk for mortality compared to normal weight women.

Despite the negative prognostic effect of overweight/obesity on survival of other hormonally related malignancies, such as breast cancer,¹² our results suggest that overweight/obesity may be a negligible prognostic factor for ovarian cancer survival. Of note, ovarian cancer occurrence does not appear to be associated with hormonal factors related to breast and endometrial cancers. For example, oral contraceptive use protects against the incidence of both ovarian cancer³² and endometrial cancer³³ but does not appear to influence breast cancer incidence.³⁴ Similarly, hormonal therapies, such as high-dose progestin and antiestrogen formulations, used to treat breast and endometrial cancers do not always elicit the same response in ovarian cancers.³⁵

Several studies, however, have reported an inverse association between ovarian cancer survival and various BMI measures,^15,36 some within subgroups (e.g., postmenopausal women),¹⁸ although results were not always consistent across strata of overweight/obesity¹⁶ or time of BMI measurement.^17,19,23,36 Variations in study findings may be due to differences in the BMI distribution between study populations,^19,23 older populations studied,^23,31 residual confounding due to a lack of information on important covariates (e.g., reproductive factors),^16,17 abbreviated follow-up periods,^19,25 and the use of postoperative weight or weight at time of diagnosis.^15,18

Possible mechanisms through which overweight/obesity could affect ovarian cancer survival include influences on tumor growth and cell apoptosis.^31,37

–40 A limitation of these hypotheses is that many are based on in vitro studies,^38,41 which can rarely be replicated in vivo. ⁴² Apart from the influence of obesity on tumor biology, authors have speculated that obese patients may receive inadequate treatment, although several studies have demonstrated that obese patients were equally as likely as normal weight patients to receive optimal surgeries.^15,30,31

This study was subject to several limitations. The distribution of BMI in our study population limited our ability to examine the effect of obesity (BMI ≥30.0) or other definitions of obesity (e.g., class 1 obesity) on ovarian cancer survival; nonetheless, the BMI distribution in our study likely reflects both the BMI distribution of the general population at the time when the women were diagnosed with ovarian cancer and the modest association between high BMI and ovarian cancer incidence.¹⁰ Our use of self-reported weight and height when calculating BMI could have caused misclassification, especially among overweight cases, as women tend to underestimate weight and overestimate height. Next, our study lacked detailed information on regimens and effectiveness of cancer treatments received. Although unmeasured cancer treatment variables could confound our results, this is unlikely because only a limited number of treatments were available during our study period. Finally, our study population was relatively young (median age 42.6), and we were not able to examine the effect of BMI on ovarian cancer survival among older women.

The study also had several strengths. The CASH study employed a population-based design to increase the generalizability of results, our linkage with SEER allowed for a long follow-up period, usual adult and age 18 weight were used instead of weight at time of diagnosis or surgery so as to minimize the effect of weight changes related to the cancer itself or related treatments, and, finally, we were able to consider a number of important covariates, such as reproductive factors, family history of disease, presence of other comorbid conditions, and such lifestyle characteristics as smoking in relation to survival.

Despite suggestions that BMI might influence risk of developing ovarian cancer, particularly among younger women, results from studies examining the effect of BMI on survival after ovarian cancer diagnosis are inconsistent. In this study of younger women, we found no evidence of an association between BMI and ovarian cancer survival in our study population. Given the lethality of ovarian cancer, continued efforts to identify modifiable prognostic factors for ovarian cancer are greatly needed.

Footnotes

Disclosure Statement

The authors have no conflicts of interest to report.

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