Journal of the National Cancer Institute Advance Access published online on December 25, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm267
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© The Author 2007. Published by Oxford University Press.
ARTICLES |
Effect of Systemic Adjuvant Treatment on Risk for Contralateral Breast Cancer in the Women's Environment, Cancer and Radiation Epidemiology Study
Affiliations of authors: Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark (L. Bertelsen, JHO, LM, JC); Department of Preventive Medicine, University of Southern California, Los Angeles, CA (L. Bernstein, RWH, BL, DCT); Department of Epidemiology, University of Iowa, Iowa City, IA (CFL); Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (KEM); Department of Epidemiology, School of Medicine, University of California, Irvine, CA (HAC); Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York (CBB, MC, JLB); Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (BE); Department of Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, TX (MS); International Epidemiology Institute, Rockville, MD (JDB); Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (JDB); New York University School of Medicine, New York (RES)
Correspondence to: Lisbeth Bertelsen, MD, Institute of Cancer Epidemiology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark (e-mail: lisbethb{at}cancer.dk).
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ABSTRACT |
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Background: Results from randomized trials indicate that treatment with tamoxifen or chemotherapy for primary breast cancer reduces the risk for contralateral breast cancer. However, less is known about how long the risk is reduced and the impact of factors such as age and menopausal status.
Methods: The study included 634 women with contralateral breast cancer (case patients) and 1158 women with unilateral breast cancer (control subjects) from the Women's Environment, Cancer and Radiation Epidemiology Study. The women were younger than age 55 when they were first diagnosed with breast cancer during 1985–1999. Rate ratios (RRs) and 95% confidence intervals (CIs) for contralateral breast cancer after treatment with chemotherapy or tamoxifen were assessed by multivariable adjusted conditional logistic regression analyses.
Results: Chemotherapy was associated with a lower risk for contralateral breast cancer (RR = 0.57, 95% CI = 0.42 to 0.75) than no chemotherapy. A statistically significant association between chemotherapy and reduced risk for contralateral breast cancer persisted up to 10 years after the first breast cancer diagnosis and was stronger among women who became postmenopausal within 1 year of the first breast cancer diagnosis (RR = 0.28, 95% CI = 0.11 to 0.76). Tamoxifen use was also associated with reduced risk for contralateral breast cancer (RR = 0.66, 95% CI = 0.50 to 0.88) compared with no use, and the association was statistically significant for 5 years after the first diagnosis.
Conclusion: The associations between chemotherapy and tamoxifen treatment and reduced risk for contralateral breast cancer appear to continue for 10 and 5 years, respectively, after the initial breast cancer is diagnosed. Ovarian suppression may have a role in the association between chemotherapy and reduced risk for contralateral breast cancer.
Prior knowledge Breast cancer patients who are treated with tamoxifen or chemotherapy have a reduced risk for contralateral breast cancer. Study design Case–control study of women 54 years of age and younger with contralateral or unilateral nonmetastatic invasive breast cancer who were treated with tamoxifen, chemotherapy, radiotherapy, or surgery alone. Contributions Chemotherapy was associated with a reduced risk for contralateral breast cancer that continued 10 years after diagnosis. The association was stronger among women who became postmenopausal within 1 year of their first breast cancer diagnosis. Tamoxifen treatment was associated with a reduced risk for contralateral breast cancer that continued for 5 years after diagnosis. Implications Ovarian suppression may be involved in the association between reduced risk for contralateral breast cancer and chemotherapy. Limitations Although the study was restricted to nonmetastatic breast cancer, it is possible that metastases were classified as new primary breast cancers. Findings were based solely on breast cancer survivors; thus, the potential for survivor bias exists and the findings may not apply to all breast cancer patients. No adjustments for oophorectomy or ovarian radiation were performed.
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The risk for asynchronous contralateral breast cancer is two to six times greater than the risk for a first primary breast cancer in the general population of women (1). In a recent update by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) (2), which included 194 randomized treatment trials, adjuvant chemotherapy was compared with no chemotherapy. Women who were younger than 50 years when treated with chemotherapy had reduced risk of developing contralateral breast cancer (HR = 0.66; P = .003), whereas no effect was observed among women 50 years and older. The EBCTCG overview also showed that administration of tamoxifen for a median of 5 years vs no tamoxifen reduced the risk for contralateral breast cancer among women who originally had estrogen receptor (ER)-positive or ER-unknown disease (HR = 0.61; P < .001), whereas there was no impact on women who originally had ER-poor disease (2, 3). Overall risk reductions of 30%–80% for contralateral breast cancer have been reported in observational studies of women treated for breast cancer with chemotherapy (4–7) and studies of women treated with tamoxifen (8–9). Cytostatic drugs are believed to work by eradicating unrecognized microscopic tumors and inducing menopause in premenopausal women (10). Tamoxifen, a selective ER modulator, exerts an antiestrogenic effect on breast tissue by binding to ERs, thus delaying or hampering the development of a new breast cancer (11).
Although chemotherapy and tamoxifen seem to act independently to protect against the development of contralateral breast cancer, little is known about the duration of beneficial effects, whether they vary by host- and tumor-related factors (6,12), and whether the therapeutic benefit is due to the induction of early menopause. With particular emphasis on these issues, we investigated the association between chemotherapy and tamoxifen and the risk for contralateral breast cancer among women who were diagnosed with a first breast cancer when they were younger than age 55 and who participated in the multicenter Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study (13).
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Subjects and Methods |
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Study Population
Women with contralateral breast cancer (case patients) and women with unilateral breast cancer (control subjects) were recruited to participate in the WECARE Study (13). The participants were identified through five population-based cancer registries: four in the United States (the Los Angeles County Cancer Surveillance Program, the Cancer Surveillance System of the Fred Hutchinson Cancer Research Center [Seattle region], the State Health Registry of Iowa, and the Cancer Surveillance Program of Orange County/San Diego-Imperial Organization for Cancer Control [Orange County/San Diego]), all of which participate in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program, and one in Denmark (the Danish Breast Cancer Cooperative Group Registry supplemented with data from the Danish Cancer Registry).
All first primary breast cancers were invasive without distant metastases and were diagnosed between January 1, 1985, and December 31, 1999, in women aged 54 years or younger at diagnosis. Case patients were eligible for the study if a second primary breast cancer (invasive or in situ) was diagnosed at least 12 months after the initial diagnosis. Case patients were required to have resided in the same reporting area at the time of diagnosis of both cancers and to have had no prior or intervening cancer diagnosis between their first and second primary breast cancers. The second primary breast cancer had to have been diagnosed no later than December 31, 2001. Control subjects had no contralateral breast cancer during the interval between the matched case patient's first and second breast cancers ("at-risk" period), had no prophylactic mastectomy during the at-risk period, and had no prior or intervening cancer diagnoses. The reference date for case patients was the date of diagnosis of the second primary breast cancer and that for control subjects was defined by adding the at-risk period for the matched case patient to the date of diagnosis for the primary breast cancer for the control subject. All women had to be alive at the time of interview. Two control subjects were individually matched to each woman with contralateral breast cancer on year of birth (in 5-year strata), year of diagnosis (in 4-year strata), registry region, and race and were counter matched on radiotherapy (yes or no). As implemented in the WECARE Study, the counter-matching design specifies that each case–control set consists of two women who had received radiotherapy based on cancer registry records and one woman who had not; that is, control subjects are sampled from the pool of eligible control subjects so that the case–control set will have this structure (13,14). Counter matching was used to improve the statistical efficiency of the main study, which was designed to assess whether genetic factors involved in DNA repair, in combination with radiation exposure, were associated with an increased risk for contralateral breast cancer (13). Sampling weights were calculated to account for the sampling probability of counter matching.
Medical records were retrieved to obtain detailed information on the treatment of the first breast cancer (chemotherapy, hormonal therapy, and radiotherapy) during the at-risk period. The information on chemotherapy and hormonal therapy included dates of administration, reason for treatment (primary disease, recurrence, other, or unknown), and type of drug. The two standard chemotherapy regimens most commonly used during the study period were based on cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) and on cyclophosphamide, epirubicin/adriamycin, and 5-fluorouracil (CEF/CAF). The remaining chemotherapy regimens were categorized as either "other anthracycline-based regimens" or "other." The characteristics of the first breast tumors were extracted from tumor registry records, and further data were obtained from hospital and physician medical records.
Participants were interviewed by telephone with a structured questionnaire to obtain information on known breast cancer risk factors, such as family history of breast cancer, reproductive history, use of hormones, alcohol intake, and body mass index (BMI). In addition, for the subset of women for whom information from medical records on chemotherapy and/or hormonal therapy was missing, the information was obtained during the telephone interview with the participant. All participants provided written informed consent before enrollment into the WECARE Study, and the research protocol was approved by the respective institutional review boards and by the ethical committee system in Denmark.
Of the 998 case patients and 2112 control subjects who were eligible and approached for agreement to participate in the study, 708 (71%) case patients and 1399 (66%) control subjects were enrolled. Most (79%) of the second primary tumors of the enrolled case patients were invasive.
We then excluded women who had been treated with chemotherapy and/or hormonal therapy for a recurrence of their first primary breast cancer and women with missing information on covariates used in the statistical models. Women who were treated for a recurrence were identified based on medical record information; if the reason for treatment was unknown, women were considered to have been treated for a recurrence if systemic treatment was initiated more than 1 year after the primary diagnosis of breast cancer. In total, we excluded 191 women treated for a recurrence (59 case patients and 132 control subjects): 57 women treated with chemotherapy, 105 women who received hormonal therapy, and 29 women who received both chemotherapy and hormonal therapy. We further excluded six women (two case patients and four control subjects) with missing information on potential confounders (see below). All these exclusions further resulted in the elimination of 13 case patients for whom all control subjects were excluded and 105 control subjects (17 single control subjects and 44 pairs of control subjects). The final study population therefore consisted of 1792 subjects (634 case patients with contralateral breast cancer and 1158 control subjects with unilateral breast cancer, including 524 triplets [one case patient, two control subjects] and 110 pairs [one case patient, one control subject]). As already mentioned, when information on chemotherapy and/or hormonal therapy was missing in the medical record, this information was obtained during the telephone interview. After the exclusions, 4% of all subjects had information on chemotherapy from the interview and 0.1% of all subjects had information on tamoxifen use from the interview.
Statistical Methods
Rate ratios (RRs) and corresponding 95% confidence intervals (CIs) were estimated by multivariable conditional logistic regression models using the TPHREG procedure in SAS release 9.1 (SAS Institute, Inc., Cary, NC), which accounted for the counter-matched design by including weights as an "offset" term in the model (13,14). In the initial analyses, rate ratios were calculated for women who received chemotherapy only, tamoxifen only, or combinations of treatment, with women who had undergone surgery only as the referent group. In addition, the effects of chemotherapy and tamoxifen were estimated separately by fitting univariate and multivariable conditional logistic regression models that included women who had never received chemotherapy or hormonal therapy, respectively, as the referent groups. In the latter models, we investigated the impact of chemotherapy and tamoxifen treatment on the risk for contralateral breast cancer by intervals of time since diagnosis of the first breast cancer (1–5, >5 to 10, or >10 years) and by host and tumor characteristics (age at first diagnosis of breast cancer [<45, 45–49, or 50–54 years], menopausal status 1 year after first breast cancer diagnosis [premenopausal, pre- to postmenopausal, or postmenopausal], family history of breast cancer among first degree relatives [yes, no, or adopted], BMI [<18.50, 18.50–24.99, 25.00–29.99, or 
30.00 kg/m2] (15), histology [lobular or ductal/other], and ER status of the first breast cancer [positive, negative, or unknown/borderline results]). We tested for statistical heterogeneity of treatment effects on risk for contralateral breast cancer across strata of these characteristics. The effect of different chemotherapy regimens was also assessed. Tamoxifen may have a considerable carry-over benefit that lasts some years after termination of the treatment (16). Therefore, we investigated impact of duration of tamoxifen use and time since last use of tamoxifen among women with more than 10 years between the first breast cancer diagnosis and the reference date. Finally, we explored whether an interaction between use of tamoxifen and chemotherapy was present.
In the multivariable analyses, we included exact age at diagnosis of the first primary breast cancer (continuous), family history of breast cancer among first-degree relatives (yes, no, or adopted), lobular histology of the first breast cancer (yes or no), and stage of first breast cancer (local or regional). The analyses for the effect of chemotherapy included terms for radiotherapy (yes or no) and hormonal therapy (yes or no). The analyses examining the effect of tamoxifen included terms for radiotherapy (yes or no), chemotherapy (yes or no), and other hormonal therapy than tamoxifen (yes or no). All statistical tests were two-sided; P values less than .05 were considered as statistically significant.
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Results |
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The distribution of case patients and control subjects by study center, exposure to radiotherapy (yes or no), and the extent of the first breast cancer diagnosis is shown separately for all 2107 women who participated in the WECARE Study and for the 1792 women eligible for the present analysis (Table 1). The relative risk for contralateral breast cancer among women who were excluded in this study because they had been treated with chemotherapy and/or hormonal therapy for a recurrence compared with women who had not been treated for a recurrence was 0.76 (95% CI = 0.52 to 1.11) (data not shown in tables). The median age at diagnosis of a first breast cancer of the women included in this study was 46 years (range = 23–54 years). The median interval between first breast cancer and the reference date was 4 years (range = 1–16 years).
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In the initial analyses, women who had undergone surgery as the only breast cancer treatment were used as the referent group (Table 2). Chemotherapy was the only adjuvant treatment used for 92 (15%) of the case patients and 86 (7%) of the control subjects, and a reduced risk for contralateral breast cancer was associated with chemotherapy only (RR = 0.53, 95% CI = 0.34 to 0.83). Tamoxifen was the only adjuvant therapy used for 36 (6%) of the case patients and 20 (2%) of the control subjects. No association between the risk for contralateral breast cancer and tamoxifen use only was observed (RR = 0.99, 95% CI = 0.50 to 1.97). The combination of tamoxifen and chemotherapy was received by 36 (6%) of the case patients and 116 (10%) of the control subjects and was associated with a decreased risk for contralateral breast cancer (RR = 0.43, 95% CI = 0.23 to 0.80).
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The interaction between tamoxifen and chemotherapy was explored in another model in which the combination of no use of tamoxifen and no use of chemotherapy was the referent group. In this model, the combinations of no tamoxifen and use of chemotherapy (RR = 0.59, 95% CI = 0.43 to 0.82) and receiving both tamoxifen and chemotherapy (RR = 0.36, 95% CI = 0.23 to 0.56) were associated with a reduced risk for contralateral breast cancer; for the combination of tamoxifen use and no chemotherapy, an association was suggested (RR = 0.74, 95% CI = 0.50 to 1.08). The P value was .43 for the interaction between tamoxifen and chemotherapy.
Women who had received chemotherapy had a lower overall risk for contralateral breast cancer than those who had never received chemotherapy (RR = 0.57, 95% CI = 0.42 to 0.75) (Table 3). Although the tests for heterogeneity of the risk estimates did not reach statistical significance, the association with chemotherapy appeared to be modified by time since and age at first diagnosis, menopausal status 1 year after the first diagnosis, and BMI. The association with chemotherapy was statistically significant both when the time since diagnosis of the first breast cancer was 1–5 years (RR = 0.61, 95% CI = 0.44 to 0.86) and when it was >5 to 10 years (RR = 0.43, 95% CI = 0.27 to 0.68), whereas the risk was close to unity more than 10 years after the first breast cancer diagnosis (RR = 0.98, 95% CI = 0.41 to 2.35). Highly statistically significant reductions in the risk for contralateral breast cancer were seen for women who were 45–49 years of age at the time of first diagnosis (RR = 0.42, 95% CI = 0.27 to 0.66) and for women who became postmenopausal within the first year after the primary diagnosis and breast cancer treatment (RR = 0.28, 95% CI = 0.11 to 0.76). The association of reduced risk with chemotherapy varied somewhat by BMI at the time of diagnosis of the first breast cancer (Table 3). When the subgroups of women with BMI less than 30 kg/m2 were combined, chemotherapy was associated with a statistically significantly reduced risk for contralateral breast cancer (RR = 0.54, 95% CI = 0.40 to 0.72), whereas there was no association among women whose BMI was 30 kg/m2 or greater at the time of diagnosis (RR = 0.89, 95% CI = 0.48 to 1.65) (P = .09 for test for heterogeneity) (categories different from those shown in Table 3). No variations in association between chemotherapy and the risk for contralateral breast cancer by other host and tumor characteristics were noted (Table 3). The association of chemotherapy and reduced contralateral breast cancer risk did not vary statistically significantly among the major chemotherapy regimens, for example, CMF or CEF/CAF, although no association with other anthracycline-based regimens was evident (RR = 0.90, 95% CI = 0.55 to 1.49) (Table 4).
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Of the 502 breast cancer patients who had received hormonal therapy for their first breast cancer, 489 had received tamoxifen and 13 had received aromatase inhibitors, other selective ER modulators, testosterone, or progesterone. The median duration of tamoxifen use among the 383 women with known duration was 2.7 years (5th percentile = 3 months, 95th percentile = 6.8 years), and the time since last use was 1.9 months (5th percentile = 0, 95th percentile = 5.6 years). The overall risk for contralateral breast cancer among women who had been treated with tamoxifen was reduced compared with that in women who had not received tamoxifen (RR = 0.66, 95% CI = 0.50 to 0.88) (Table 5). Tamoxifen use was associated with a statistically significantly decreased risk for contralateral breast cancer only when the time since first breast cancer diagnosis was limited to 5 years (RR = 0.55, 95% CI = 0.39 to 0.78), although a decreased risk was suggested in the >5-to-10-year interval (RR = 0.74, 95% CI = 0.43 to 1.28). Women who were treated with tamoxifen and were followed-up for more than 10 years after diagnosis of a first breast cancer had an increased risk for contralateral breast cancer (RR = 3.84, 95% CI = 1.11 to 13.3). Although the test for heterogeneity of the risk estimates did not reach statistical significance, the association of reduced risk of contralateral breast cancer with tamoxifen appeared to be modified by age, with the most marked decrease seen among women younger than 45 years (RR = 0.49, 95% CI = 0.30 to 0.82). Among women whose first breast cancer was ER-positive, tamoxifen treatment was associated with a statistically significantly reduced risk of contralateral breast cancer (RR = 0.60, 95% CI = 0.42 to 0.85). No clear effects of the other host and tumor characteristics were seen on the risk for contralateral breast cancer risk associated with tamoxifen treatment.
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Women who were diagnosed with their first breast cancer more than 10 years before the reference date used tamoxifen for a median of 4.8 years (5th percentile = 6 months, 95th percentile = 9.2 years), and the median time since last use was 4.9 years (5th percentile = 1 day, 95th percentile = 11.4 years). Among these women, the RR was 0.80 (95% CI = 0.66 to 0.98) for each 6-month increase in duration of tamoxifen use (Ptrend = .03), and the RR was 1.15 (95% CI = 0.97 to 1.35) for each 6-month increase in time since last use (Ptrend = .10; data not shown).
Because the results could potentially differ between US and Danish women, we performed a sensitivity analysis in which we excluded the 509 Danish subjects (173 case patients and 336 control subjects). The overall associations of contralateral breast cancer risk with chemotherapy (RR = 0.57, 95% CI = 0.40 to 0.81) and tamoxifen treatment (RR = 0.65, 95% CI = 0.48 to 0.89) for US subjects alone were similar to those of US and Danish subjects combined.
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Discussion |
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We found that the risk for contralateral breast cancer was reduced by 35%–40% in women who were first diagnosed with breast cancer when they were younger than 55 years if they were treated with either chemotherapy or tamoxifen, compared with women who had never received such treatment. The inverse association between contralateral breast cancer risk and chemotherapy appeared to persist for as long as 10 years, whereas that with tamoxifen use appeared to be shorter. The association with chemotherapy was stronger among women who became postmenopausal within 1 year of the first diagnosis and weaker among obese women than nonobese women.
Some previous observational studies reported a 30%–70% reduction in the risk for contralateral breast cancer after chemotherapy (4–7), whereas other studies reported no effect (9,17). In none of these studies was risk by time since diagnosis of the first breast cancer addressed, perhaps because most of the studies had low statistical power for assessing long-term risks. Our finding of no indication of a reduced risk 10 or more years after diagnosis of the first breast cancer suggests a diminution of the inverse association between chemotherapy and the risk for contralateral breast cancer, but the data were limited by small numbers. The main effect of chemotherapy could be the eradication of small breast cancer foci in the contralateral breast; however, the low risk of contralateral breast cancer observed among women who became postmenopausal within 1 year after the first breast cancer diagnosis suggests that an endocrine effect of chemotherapy by induction of ovarian failure also contributes to reduce the risk of contralateral breast cancer. The endocrine effect would also be expected to diminish over time due to the occurrence of natural menopause among those not receiving chemotherapy. Furthermore, the EBCTCG overview (2,3) showed that chemotherapy had a protective effect on contralateral breast cancer only among women younger than 50 years, that is, among women who may experience chemotherapy-induced premature menopause. A weaker association between contralateral breast cancer risk and chemotherapy among women with a higher BMI was suggested by one case–control study (6) and by our results. Several explanations for the attenuation of the association have been proposed, including that the dose of chemotherapy for obese breast cancer patients is systematically reduced to avoid toxic reactions (18), that the probability of amenorrhea associated with chemotherapy is reduced in premenopausal obese breast cancer patients, and that, if menopause is induced, the estrogen production in peripheral adipose tissue counteracts the beneficial effects of menopause (19).
The reduction in the risk for contralateral breast cancer associated with tamoxifen use compared with no use observed in our study is compatible with the previous observational studies (8–9). Although we saw no reduced risk of contralateral breast cancer among women receiving tamoxifen alone compared with women who had undergone surgery, indicating that tamoxifen must be supplemented by chemotherapy for the association to occur, this finding of no association between tamoxifen use alone and contralateral breast cancer should be interpreted with caution. First, the number of women who received tamoxifen only (36 case patients and 20 control subjects) was small, and the confidence intervals for this finding were wide; thus, a risk reduction as low as 50% cannot be rejected. Second, we found no statistically significant interaction between treatment with chemotherapy and tamoxifen. Finally, use of tamoxifen without chemotherapy was associated with reduced risk for contralateral breast cancer in three previous studies (17,20,21), although in two of the studies the reduction was not statistically significant (17,20).
To our knowledge, no observational studies have investigated the effect of tamoxifen on contralateral breast cancer by time since diagnosis of the first breast cancer, and the clinical studies of late effects of tamoxifen focused on recurrence and mortality. There is no indication so far from the randomized International Breast Cancer Intervention Study Trial (22), the Royal Marsden Trial (23), or the National Surgical Adjuvant and Bowel Project Breast Cancer Prevention Trial (P-1) Study (24) that the prophylactic effect of tamoxifen treatment among high-risk women diminishes over time. However, in these studies, women treated with tamoxifen had no previous breast cancer, the outcome was a first primary breast cancer, and duration of tamoxifen treatment was standardized to 5 or 8 years, that is, settings differed from those of our study. The increased risk for contralateral breast cancer that we observed 10 years after the first breast cancer among tamoxifen users compared with nonusers should be interpreted cautiously because it is based on relatively few women. Although the concordance in ER status between a first and a second breast cancer is uncertain (25,26), it has been shown that tamoxifen has the most favorable effect on contralateral breast cancer risk when the first breast cancer is ER-positive (2,20), which is consistent with our findings. Based on results for women with more than 10 years between the first primary breast cancer and the reference date, it appeared that a longer duration of tamoxifen use is associated with a lower risk for contralateral breast cancer than a shorter duration. Evidence from previous studies also suggests that longer treatment times with tamoxifen are more effective in preventing contralateral breast cancer than shorter treatment times (8,27,28). Overall, our observations suggest that tamoxifen users experience a reduced rate of contralateral breast cancers but raise questions as to how long the association persists.
Although we restricted this study to women diagnosed with localized or regional disease and specified a minimum of 1 year between the first and second breast cancer, the possibility that metastases were misclassified as new primary breast cancers remains. However, recent studies that have compared pairs of first primary and contralateral breast tumors from the same patients using molecular profiling suggest that most diagnosed contralateral breast cancers are independent occurrences of the disease (29–31). All case patients and control subjects had to be alive at date of interview, so our findings are based on breast cancer survivors, and we cannot rule out the potential for a survival bias in our results. The restriction to survivors also means that the results might not apply to all breast cancer patients. Finally, we were not able to control for potential confounding of bilateral oophorectomy and ovarian radiation.
The strengths of our study include its large sample size, the population-based approach, and detailed abstraction of medical records to confirm the cancer-free interval for control subjects and to document the treatment history of both case patients and control subjects.
In summary, our results suggest that a substantial reduction in the risk for contralateral breast cancer is associated with chemotherapy and tamoxifen treatment among breast cancer patients diagnosed when they were younger than 55 years and that the reduction may last for up to 10 years after initial breast cancer diagnosis. Ovarian suppression caused by chemotherapy may have a role in the association, possibly in combination with a cytotoxic effect on prevalent subclinical contralateral breast cancers.
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Funding |
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National Institutes of Health (U01 CA083178 [GenBank] , R01 CA097397 [GenBank] , and R01 CA114236 [GenBank] ); The collection of cancer incidence data for the two California data centers was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885. SEER Program of the National Cancer Institute (N01 PC35139 to University of Southern California and N02 PC15105 to Public Health Institute); National Program of Cancer Registries of the Centers for Disease Control and Prevention (#U55/CCR921930-02 to Public Health Institute). Case ascertainment was additionally supported by the SEER Program of the National Cancer Institute under contract N01 PC35142 in Seattle and N01 PC35143 in Iowa.
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NOTES |
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The ideas and opinions expressed in this article are those of the authors, and no endorsement by the California Department of Health Services is intended or should be inferred. Further, the contents do not necessarily represent the official views of the US Government.
Corporate authorship list of the WECARE Study Collaborative Group:
Principal investigator: J. L. Bernstein, PhD; Coinvestigators named on grant: H. Anton-Culver, PhD, C. B. Begg, PhD, L. Bernstein, PhD, J. D. Boice Jr, PhD, Anne-Lise Børresen-Dale, PhD, M. Capanu, PhD, Patrick Concannon, PhD, Richard A. Gatti, PhD, R. W. Haile, DrPH, PhD, B. M. Langholz, PhD, C. F. Lynch, MD, PhD, K. E. Malone, PhD, J. H. Olsen, MD, DMSc, Barry Rosenstein, PhD, R. E. Shore, PhD, rPH, M. Stovall, PhD, D. C. Thomas, PhD, W. Douglas Thompson, PhD.
Coordinating centers: Memorial Sloan-Kettering Cancer Center, New York—J. L. Bernstein, PhD (WECARE Study P. I.), Xiaolin Liang, MD, MS (Informatics Specialist), Abigail Wolitzer, MSPH (Project Director); National Cancer Institute, Bethesda, MD—Daniela Seminara, PhD, MPH (Program Officer).
Data collection centers: University of Southern California, Los Angeles, CA—L. Bernstein, PhD (P. I.), Laura Donnelly-Allen (Project Manager); Danish Cancer Society, Copenhagen, Denmark—J. H. Olsen, MD, DMSc (P. I.), Lene Mellemkjær, PhD, MSc (Project Manager); University of Iowa, Iowa City, IA—C. F. Lynch, MD, PhD (P. I.), Jeanne DeWall, MA (Project Manager); Fred Hutchinson Cancer Research Center, Seattle, WA—K. E. Malone, PhD (P. I.), Noemi Epstein (Project Manager); University of California at Irvine, Irvine, CA—H. Anton-Culver, PhD (P. I.), Joan Largent, PhD, MPH (Project Manager).
Radiation measurement: The University of Texas M. D. Anderson Cancer Center, Houston, TX—M. Stovall, PhD (P. I.), Susan Smith, MPH (Quality Assurance Dosimetry Supervisor); New York University, New York—R. E. Shore, PhD, DrPH (Epidemiologist); International Epidemiology Institute, Rockville, MD, and Vanderbilt University, Nashville, TN—J. D. Boice Jr, ScD (Consultant).
Biostatistics core: University of Southern California, Los Angeles, CA—B. M. Langholz, PhD, D. C. Thomas, PhD; Memorial Sloan-Kettering Cancer Center, New York—C. B. Begg, PhD, M. Capanu, PhD; University of Southern Maine, Portland, ME—W. Douglas Thompson, PhD (P. I.).
External advisors: Stanford University, Palo Alto, CA—Alice Whittemore, PhD.
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REFERENCES |
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1. Chen Y, Thompson W, Semenciw R, Mao Y. Epidemiology of contralateral breast cancer. Cancer Epidemiol Biomarkers Prev. (1999) 8:855–861.
2. The Early Breast Cancer Trialists' Collaborative Group. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet (2005) 365:1687–1717.[CrossRef][Web of Science][Medline]
3. Annex—Figures 1–14 and separate Appendices to each of Tables 1–4. http://www.ctsu.ox.ac.uk/~ebctcg/systemic2000/annex.htm#Appendix%20to%20Table%201Accessed October 11, 2007.
4. Bernstein JL, Thompson WD, Risch N, Holford TR. Risk factors predicting the incidence of second primary breast cancer among women diagnosed with a first primary breast cancer. Am J Epidemiol. (1992) 136:925–936.
5. Broet P, de la Rochefordiere A, Scholl SM, et al. Contralateral breast cancer: annual incidence and risk parameters. J Clin Oncol. (1995) 13:1578–1583.
6. Horn PL, Thompson WD. Risk of contralateral breast cancer. Associations with histologic, clinical, and therapeutic factors. Cancer (1988) 62:412–424.[CrossRef][Web of Science][Medline]
7. Schaapveld M, Visser O, Louwman WJ, et al. The impact of adjuvant therapy on contralateral breast cancer risk and the prognostic significance of contralateral breast cancer: a population based study in the Netherlands. Breast Cancer Res Treat (2007) [Epub ahead of print].
8. Cook LS, Weiss NS, Schwartz SM, et al. Population-based study of tamoxifen therapy and subsequent ovarian, endometrial, and breast cancers. J Natl Cancer Inst (1995) 87:1359–1364.
9. Gajalakshmi CK, Shanta V, Hakama M. Risk factors for contralateral breast cancer in Chennai (Madras), India. Int J Epidemiol (1998) 27:743–750.
10. Walshe JM, Denduluri N, Swain SM. Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol (2006) 24:5769–5779.
11. Dutertre M, Smith CL. Molecular mechanisms of selective estrogen receptor modulator (SERM) action. J Pharmacol Exp Ther (2000) 295:431–437.
12. Dignam JJ, Wieand K, Johnson KA, Fisher B, Xu L, Mamounas EP. Obesity, tamoxifen use, and outcomes in women with estrogen receptor-positive early-stage breast cancer. J Natl Cancer Inst (2003) 95:1467–1476.
13. Bernstein JL, Langholz B, Haile RW, et al. Study design: evaluating gene-environment interactions in the etiology of breast cancer—the WECARE study. Breast Cancer Res. (2004) 6:R199–R214.[CrossRef][Web of Science][Medline]
14. Langholz B, Borgan Ø. Counter-matching: a stratified nested case–control sampling method. Biometrika (1995) 82:69–79.
15. World Health Organization. Obesity: preventing and managing the global epidemic (2000) Geneva, Switzerland: WHO Technical Report Series.
16. Peto R. Five years of tamoxifen—or more? J Natl Cancer Inst (1996) 88:1791–1793.
17. Fowble B, Hanlon A, Freedman G, Nicolaou N, Anderson P. Second cancers after conservative surgery and radiation for stages I–II breast cancer: identifying a subset of women at increased risk. Int J Radiat Oncol Biol Phys. (2001) 51:679–690.[CrossRef][Web of Science][Medline]
18. Griggs JJ, Sorbero ME, Lyman GH. Undertreatment of obese women receiving breast cancer chemotherapy. Arch Intern Med (2005) 165:1267–1273.
19. Carmichael AR, Bates T. Obesity breast cancer: a review of the literature. Breast (2004) 13:85–92.[CrossRef][Web of Science][Medline]
20. Li CI, Malone KE, Weiss NS, Daling JR. Tamoxifen therapy for primary breast cancer and risk of contralateral breast cancer. J Natl Cancer Inst (2001) 93:1008–1013.
21. Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst (1996) 88:1673–1682.
22. Cuzick J, Forbes JF, Sestak I, et al. Long-term results of tamoxifen prophylaxis for breast cancer—96 months follow-up of the randomised IBIS-I trial. J Natl Cancer Inst (2007) 99:272–282.
23. Powles TJ, Ashley S, Tidy A, Smith IE, Dowsett M. Twenty-year follow-up of the Royal Marsden randomized, double-blinded tamoxifen breast cancer prevention trial. J Natl Cancer Inst (2007) 99:283–290.
24. Fisher B, Constantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst (2005) 97:1652–1662.
25. Swain SM, Wilson JW, Mamounas EP, et al. Estrogen receptor status of primary breast cancer is predictive of estrogen receptor status of contralateral breast cancer. J Natl Cancer Inst (2004) 96:516–523.
26. Arpino G, Weiss HL, Clark GM, Hilsenbeck SG, Osborne CK. Hormone receptor status of a contralateral breast cancer is independent of the receptor status of the first primary in patients not receiving adjuvant tamoxifen. J Clin Oncol (2005) 23:4687–4694.
27. The Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet (1998) 351:1451–1467.[CrossRef][Web of Science][Medline]
28. Swedish Breast Cancer Cooperative Group. Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer. J Natl Cancer Inst (1996) 88:1543–1549.
29. Kollias J, Man S, Marafie M, et al. Loss of heterozygosity in bilateral breast cancer. Breast Cancer Res Treat (2000) 64:241–251.[CrossRef][Web of Science][Medline]
30. Imyanitov EN, Suspitsin EN, Grigoriev MY, et al. Concordance of allelic imbalance profiles in synchronous and metachronous bilateral breast carcinomas. Int J Cancer (2002) 100:557–564.[CrossRef][Web of Science][Medline]
31. Regitnig P, Ploner F, Maderbacher M, Lax SF. Bilateral carcinomas of the breast with local recurrence: analysis of genetic relationship of the tumors. Mod Pathol (2004) 17:597–602.[CrossRef][Web of Science][Medline]
Manuscript received June 19, 2007; revised October 16, 2007; accepted November 8, 2007.
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J Natl Cancer Inst 2008 100: 1.
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