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Originally published as Ann Surg Oncol Early Release 10.1245/ASO.2003.03.068 on October 13, 2003

Annals of Surgical Oncology 10:1031-1038 (2003)
© 2003 Society of Surgical Oncology
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ORIGINAL ARTICLES

Breast Cancer in Women With Recent Exposure to Fertility Medications is Associated With Poor Prognostic Features

Nava Siegelmann-Danieli, MD, Ada Tamir, DSc, Hanna Zohar, RN, Moshe Z. Papa, MD, Lika L. Chetver, MD, Zehava Gallimidi, MD, Moshe E. Stein, MD and Abraham Kuten, MD

From the Department of Hematology and Oncology (NS-D), Geisinger Medical Center, Danville, Pa, USA; Department of Community Medicine and Epidemiology (AT), Technion Institute of Technology and The Bruce Rappaport Faculty of Medicine, Haifa, Israel; Departments of Oncology (LLC, HZ, MES, AK, MZP) and Radiology (ZG), Rambam Medical Center, Haifa, Israel; and Department of Surgical Oncology at the Sheba Medical Center, Tel-Aviv, Israel.

Correspondence: Address correspondence and reprint requests to: Nava Siegelmann-Danieli, MD, Department of Hematology and Oncology, Geisinger Medical Center, Danvile, PA 19822-2001; Fax: 570-271-6542; E-mail: nsdanieli{at}geisinger.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background: Fertility drug therapy (FDT) induces supraphysiologic endogenous estrogen production and might transiently increase breast cancer risk. Tumors developing following FDT exposure have not been extensively studied.

Methods: Thirty-eight breast cancer patients with 40 primary tumors and with history of FDT exposure were identified and compared with two other breast cancer groups: women with pregnancy-associated breast cancer (PABC, 22 patients with 23 tumors) and premenopausal women born during same calendar years and not exposed to hormonal manipulations or recent pregnancy (controls, 192 patients with 201 tumors). Patients were diagnosed and treated mostly during the last decade.

Results: Compared with controls, tumors of patients with FDT exposure presented at advanced stages (P < .005), were more likely to be estrogen or progesterone receptor negative (P < .03) and of poor histology grade (P <.0002). Aggressive features predominated among women diagnosed within 2 years of an FDT cycle (P <.05). FDT and PABC groups shared similarities. With a median follow-up of 43 months, relapse-free and cancer-free survival rates were significantly reduced in the FDT and PABC groups (P < .01 and P < .01, respectively). Multivariate analysis revealed only treatment-defined tumor stage (operable, locally advanced, or metastatic) as predictive of survival (P < .0001).

Conclusion: Breast tumors in women with recent FDT exposure present with poor prognostic features and share similarities with PABC. Survival is stage dependent.

Key Words: Breast cancer • Fertility • Clomiphene citrate • Human menopausal gonadotropins


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Breast cancer occurrence has been linked with reproductive factors and prolonged lifetime exposure to estrogen, suggesting that estrogen plays a major role in disease development.1–2 Disease risk increases with age and is most commonly found in women in the postmenopausal years. A transient peak occurring after the first full-term pregnancy, however, suggests that some younger women are susceptible to the effect of excessive estrogen exposure.3–5 Laboratory models propose that at least three mechanisms are responsible for estrogen carcinogenicity, including receptor-mediated stimulation of cell proliferation, direct genotoxic effect by estrogen metabolites, and a compromised DNA repair system.6

Endogenous estradiol production is cyclic during reproductive years, peaking to 400 pg/mL per follicle during the follicular phase and reaching 6 to 40 ng/mL on week 36 of pregnancy.7 Fertility drug therapy (FDT) induces multiple folliculogenesis and it is associated with a rapid increase in estradiol production during 1 to 2 weeks of therapy. The effect is proportional to the number of recruited follicles; is relatively modest with the use of clomiphene citrate, but can be significant with human menopausal gonadotropins (HMG). A recent publication from Australia showed a transient increase in breast cancer risk following HMG exposure in a cohort of 29,700 infertile women, only two thirds of whom were exposed to HMG as part of an in vitro fertilization (IVF) procedure.8 During the first year of HMG therapy, the relative risk (RR) for disease development was 1.96, with 17 cases observed versus 8.7 expected. Breast cancer risk did not persist, however, with a longer follow-up of 7 years. It should be mentioned, however, that some known risk factors for breast cancer (e.g., family history of breast cancer, prior breast biopsy, and findings of atypical ductal hyperplasia or lobular carcinoma in situ)1 were not included in this study’s risk analysis.

Tumor features of patients with histories of FDT exposure have not been extensively studied. The Australian series suggests a larger proportion of tumors measuring 2 cm or more in greatest dimension among women with recent FDT exposure (50% vs. 38% in recently vs. not recently exposed women).8 A French series of 32 patients previously exposed to FDT failed to define unique tumor features.9 The latter, however, did not analyze tumors according to time interval elapsed since the last FDT cycle, nor did it compare them with non-FDT-related tumors.

The present study describes demographics, tumor features, and clinical outcome in breast cancer patients previously exposed to FDT, and treated in our institution, mostly during the 1990s. These women were compared with two other patient groups: women with pregnancy-associated cancers (thought to be diagnosed in association with physiologically elevated estrogen) and premenopausal patients with no recent pregnancy or prior hormonal manipulation (controls).


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Patients
Fertility Drug Therapy Group
All new breast cancer patients who had a history of FDT exposure (clomiphene citrate, HMG, or both) were included in this group. Women with a history of exposure to FDT who presented in association with recent pregnancy were also included, as they were assumed to have been exposed to excessive estrogen levels earlier on in their pregnancies or during prior FDT cycles. Tumor registry secretaries interviewed all new patients referred to the oncology clinics at the Rambam Medical center (a tertiary medical center) from September 1997 to April 2000 at time of first clinic visit. They used a questionnaire detailing known risk factors for breast cancer and a history of FDT exposure to identify FDT-exposed patients. Identified patients were further interviewed (NSD or HZ) regarding details of FDT use (see patient characteristic below). Patients diagnosed between 1987 and August 1997 were considered to be retrospectively identified, although most were listed soon after diagnosis by the medical team running the breast clinic during these years, who interviewed all patients at time of first clinic visit regarding gynecology history and prior FDT exposure. FDT exposure and details were confirmed by personal interview in all living patients (HZ or NSD) and by chart review for those who died from their disease. Nineteen women were identified between September 1997 and April 2000; 19 patients (2 of whom were diagnosed with bilateral breast cancer) were identified for the period of 1989 to August 1997.

Pregnancy-associated Breast Cancers Group
The pregnancy-associated breast cancer (PABC) group included women diagnosed during pregnancy or within 1 year to delivery and who were not previously exposed to FDT. The identification method was identical to that of FDT-exposed patients. Totals for eight patients were identified between September 1997 and April 2000; 14 women (including 1 with bilateral breast cancer) were listed during the years 1989 to August 1997.

Controls
Premenopausal women with breast cancer who were born during the same calendar years and identified through computerized institutional registry data (which was complete for patients diagnosed between January 1994 and August 1997) were the controls. These women were diagnosed more than a year from their recent pregnancy and were not exposed to FDT in the past.

Patient Characteristics
The following parameters were abstracted: demographics, family history of cancer in first-degree and second-degree members, oral contraceptive use for at least 6 months, current smoking status, and obstetric history. All living FDT-exposed patients were interviewed regarding details of medication used, treatment duration, and infertility cause as reported to the patients by their gynecologist (ovulatory dysfunction, male factor, fallopian tube obstruction and unexplained or unknown cause). Data on genetic tests for the common Ashkenazi BRCA1/2 mutations (BRCA1 185delAG and 5328insC, BRCA2 6174delT) were abstracted from the medical charts for Jewish patients of Ashkenazi or combined (Ashkenazi—Sephardi) origin.

Tumor Features
Abstracted data included staging method (pathologic vs. clinical), stage according to the American Joint Committee on Cancer-International Union Against Cancer cancer staging manual (5th edition, 1997), tumor size in centimeters, number of axillary nodes involved and total number removed, histology type and grade, and hormone-receptor status (by immunohistochemistry or dextran-coated charcoal methods).

Treatment
Data included primary surgery (breast-conserving operation vs. mastectomy, with axillary node dissection in all curative surgeries); setting at which systemic therapy was applied (none, adjuvant, neoadjuvant, or metastatic); whether combination chemotherapy included anthracyclines (doxorubicin or epirubicin) or was CMF (cyclophosphamide, methotrexate and 5-flourouracil) based, breast irradiation, and hormone therapy (mostly with tamoxifen [20 mg/day for 5 years]). Adjuvant treatment recommendations were stage and hormone receptor dependent in all patients. Neoadjuvant approach was reserved for patients with locally advanced and mostly inoperable tumors. Patients treated during pregnancy received doxorubicin and cyclophosphamide, with or without 5-flourouracil, during the second or third trimesters of pregnancy. The breast was irradiated in all nonpregnant patients who had breast-conserving operations (50 Gy to the breast, 10 to 20 Gy boot to tumor-bed, in standard fractionation of 2 Gy/day). Radiation policy indicated lymphatic-region radiation for patients with four or more involved nodes or with gross extracapsular extension, and postmastectomy irradiation for patients with large primary tumors, close or positive resection margins, stage III tumors, and multiple (>=4) involved nodes.

Statistical Methods
The primary outcome measures were relapse-free survival (RFS), cancer-free survival (CFS), and overall survival (OS). Follow-up, relapse, and survival were calculated from time of diagnosis. RFS and CFS analysis were restricted to patients with localized tumors, including those with supraclavicular node metastases, treated in a curative intent with systemic therapy (adjuvant or neoadjuvant) and definitive surgery. An event for RFS was defined by the first local or systemic relapse. An event for CFS was defined by evidence of distant metastatic disease or by the persistence of local tumor at the last follow-up. Thus, women with local relapse who were surgically salvaged and rendered cancer-free at last follow-up were considered cancer free for CFS analysis. An OS analysis considered death from any cause. All cases of death were confirmed by the Israeli National Registry data, up to December 2000. For all outcomes, time was measured to last follow-up visit for censored patients, or to date of relapse or death for patients experiencing events. Differences in percentages for categorical demographic variables, treatment approaches, and tumor features were evaluated using either {chi}2 test or Fisher exact test. The distributions of ordinal variables were compared using the Mann-Whitney test (two groups) and the Kruskal-Wallis test (three groups). The means of continuous variables were compared using t-test (two groups) and analysis of variance (ANOVA) (three groups). All reported P-values are two-sided. Rates for RFS, CFS, and OS were estimated using the Kaplan-Meier product limit method and compared using the log-rank test. A stepwise Cox regression model was used to examine the effect of covariate on RFS, CFS, and OS. The parameters included as covariate for CFS and OS were patients’ group, treatment-defined tumor stage (operable, locally advanced, and metastatic for patients with no further or adjuvant treatment, neoadjuvant therapy, and metastatic approach, respectively), and histology grade (well and moderately differentiated tumors vs. poorly differentia- ted). Covariate for RFS analysis included patients’ group and treatment-defined tumor stage.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Study Groups
Fertility Drug Therapy Patients
Thirty-eight patients with 40 primary tumors were identified. Bilateral disease occurred synchronously in one patient and metachronously (interval of 6.5 years) in another. Year of birth for patients ranged from 1946 to 1971 (median 1957) and diagnosis date from 1987 to 2000 (median 1997). Seven patients were exposed to clomiphene alone; others reported HMG use with (15 patients) or without (10 patients) clomiphene (use unknown in 7 patients). Patients were exposed to a median of five HMG cycles (range, 1–23). The median time interval from last FDT cycle to diagnosis (2 years; range, .25–6.3 years) was available for 35 patients. The diagnosis in 13 patients was in relation to pregnancy: 7 conceived after HMG, 4 after clomiphene use, and 2 conceived spontaneously. Five patients were nulliparous (13%). The median number of pregnancies in parous women was two (range, 1–10). Data on infertility were available for 34 patients: 38% reported an unidentified cause, 24% had ovulatory dysfunction, 12% reported fallopian tube obstruction, and 26% reported a male factor alone.

Pregnancy-Associated Breast Cancer Group
Twenty-two patients were identified, one developed contralateral disease 5.4 years after diagnosis of PABC. Year of birth for patients ranged from 1953 to 1974 (median 1963) and diagnosis date from 1988 to 1999 (median 1995). The median number of pregnancies was three (range, 1–12).

Controls
Controls consisted of 192 patients with 201 primary tumors. Four patients presented with bilateral tumors synchronously and five metachronously (interval, 7 months to 4.8 years). Year of birth for patients ranged from 1946 to 1971 (median 1951) and diagnosis date (including second primaries) from 1992 to 1998 (median 1995). Twenty-two patients were nulliparous (11%). The median number of pregnancies was three (range, 0–13). The median time interval from last pregnancy to diagnosis was 12 years (range, 1.1–30 years).

Patient Characteristics
Table 1 summarizes patients’ characteristics. Median age at diagnosis was 40 years (range, 26–53), 33 years (range, 25–37), and 45 years (range, 25–53) for patients in FDT, PABC, and control groups, respectively (P < .001). The median ages at first full-term pregnancies were 29 years (range, 21–45), 26 years (range, 19–37), and 24 years (range, 17–40), respectively (P < .001). A relative overrepresentation of non-Jewish patients was seen among FDT and PABC groups compared with controls (19%, 39%, and 11%, respectively, P < .03). Among Jewish patients, a relatively lower proportion of Ashkenazi Jews was seen in the FDT group compared with controls [58% vs. 73%, respectively, nonsignificant (n.s.) difference]; this was also reflected by a lower rate of women born in Europe or the United States (19% vs. 45%, respectively, P < .01). Similar proportions were found for families with affected members and comparable oral contraceptive and tobacco exposure rates (data not shown). Although only few patients of Ashkenazi or combined Jewish origin were tested for the three common BRCA1/2 Ashkenazi mutations, no higher mutation carrier rates were detected among the FDT and PABC groups as compared with controls, despite younger ages at diagnosis. BRCA1/2 Ashkenazi mutations were detected in 3 of 8 tested FDT patients (37.5%), 1 of 5 PABC patients (20%), and 8 of 15 control patients (53%).


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  		TABLE 1. Patient characteristics in women with fertility drug therapy (FDT) exposure, pregnancy-associated breast cancer (PABC), and premenopausal women with no recent pregnancy or hormonal manipulation (Controls)a
 
Tumor Features and Treatment Approach
Patients with histories of FDT exposure generally presented with more aggressive tumors compared with controls (Table 2). This was reflected by higher rates of clinically staged tumors (25% vs. 12%, respectively, P < .04); T stage 3 and 4 (tumors measuring more than 5 cm in greatest dimension or with chest wall or dermal invasion, 27% vs. 16%, respectively); distant metastatic disease (13% vs. 3%, respectively, P < .03); poorly differentiated histology (63% vs. 32%, respectively, P < .002); and receptor-negative tumors (38% vs. 25%, respectively). Histology types (ductal, lobular, and others) and the number of axillary nodes involved in women with operable tumors did not differ significantly between the groups (data not shown). Tumors of women in the PABC and FDT groups shared similar characteristics.


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  		TABLE 2. Tumor features of women with fertility drug therapy (FDT) exposure, pregnancy-associated breast cancer (PABC), and premenopausal women with no recent pregnancy or hormonal manipulation (Controls)a
 
The FDT group had a larger proportion of women requiring a neoadjuvant or metastatic approach as compared with controls (33% vs. 13%, respectively, P < .005) and more of them had mastectomy (60% vs. 40%, respectively, P < .03), reflecting more advanced tumors at diagnosis in the FDT group (Table 3). Chemotherapy, irradiation, and hormonal therapy use did not differ significantly between the groups (data not shown).


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  		TABLE 3. Treatment approach in women with fertility drug therapy (FDT) exposure, pregnancy-associated breast cancer (PABC), and premenopausal women with no recent pregnancy or hormonal manipulation (Controls)
 
To evaluate the effect of different factors on tumor features in the FDT group, we conducted a further analysis. An association between treatment-defined tumor stage (operable, locally advanced or metastatic) and the following variables were evaluated: type of FDT used (clomiphene alone vs. HMG with or without clomiphene); infertility cause (ovulatory, male factor, and others); whether tumors were associated with recent pregnancy (yes or no); mode of patient identification (prospective or retrospective, with 19 patients in each group); and time elapsed since last FDT cycle (using the median of 2 years as a cut point). Only the latter was significantly associated with tumor features: locally advanced or metastatic tumors occurred in 9 of 18 (50%) patients diagnosed within 2 years of last FDT cycle compared with 3 of 17 patients (18%) diagnosed after longer periods (P < .05; data missing for 3 patients).

Clinical Outcome
The median follow-up period for the entire population was 43 months; 20 months (range, 2–153 months), 27 months (range, 7–137), and 45 months (range, 1–94) in FDT, PABC, and control groups, respectively. A total of 34 died, all from breast cancer. Twenty-one women were alive with disease at the last follow-up. As illustrated in Figure 1, the 5-year OS rates did not differ significantly between the groups. They were 68.9%, 71.5%, and 81.2%, for FDT, PABC, and control groups, respectively. Among FDT-exposed patients, the 5-year OS rates were 44.1% for women diagnosed within 2 years of last FDT cycles, as compared with 93.6% for patients diagnosed after longer periods (not significant, possibly because of sample size constrains). A stepwise multivariate analysis considering patient’s group, treatment-defined tumor stage (operable, locally advanced or metastatic), and histology grade revealed only treatment-defined tumor stage as predictive of OS (P < .0001). CFS and RFS analyses were restricted to 33 FDT patients, 20 PABC patients, and 181 controls, all treated in a curative intent and rendered cancer free at the end of their systemic and local therapy. RFS analysis included 51 first events, 46 occurred within 5 years of follow-up. The 5-year RFS rates were 58.5%, 54.8%, and 77.2% for patients in FDT, PABC, and control groups, respectively (Fig. 2, P < .01). Multivariate analysis revealed only treatment-defined tumor stage as predictive of PFS (P < .00001). The difference for patient group was of borderline significance (P = .058) and was only significant for PABC patients compared with controls (P < .03). Several patients with local recurrences were rendered cancer free following salvage operation and were considered cancer-free for CFS analysis. The 5-year CFS rates were 65.1%, 67.5%, and 87.1% for FDT, PABC, and control groups, respectively (Fig. 3) (P < .01, pair-wise comparisons revealing significant differences between FDT or PABC patients and controls). Multivariate analysis considering patients’ group, treatment-defined tumor stage, and histology grade demonstrated only treatment-defined tumor stage as predictive of CFS (P < .013).



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  		FIG. 1. Overall survival (OS) of breast cancer patients by study group. Estimated OS rates for 38 patients previously exposed to fertility drug therapy (FDT), 22 patients with pregnancy-associated breast cancer (PABC), and 192 patients with no recent pregnancy or hormonal manipulation (controls) using the Kaplan-Mayer methodology. The 5-year OS rates, which did not differ significantly between the groups, were 68.9%, 71.5%, and 81.2%, for FDT, PABC, and control groups, respectively.

 


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  		FIG. 2. Relapse-free survival (RFS) of breast cancer patients by study group. Estimated RFS rates for 33 patients previously exposed to fertility drug therapy (FDT), 20 patients with pregnancy-associated breast cancer (PABC), and 181 patients with no recent pregnancy or hormonal manipulation (controls), all treated in a curative intent, using the Kaplan-Mayer methodology. The 5-year RFS rates were 58.5%, 54.8%, and 77.2% for patients in FDT, PABC, and control groups, respectively, P < .01.

 


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  		FIG. 3. Cancer-free survival (CFS) of breast cancer patients by study group. Estimated CFS rates for 33 patients previously exposed to fertility drug therapy (FDT), 20 patients with pregnancy-associated breast cancer (PABC), and 181 patients with no recent pregnancy or hormonal manipulation (controls), all treated in a curative intent, using the Kaplan-Mayer methodology. The 5-year CFS rates were 65.1%, 67.5%, and 87.1% for FDT, PABC, and control groups, respectively, P < .01.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
In our series, breast cancer patients with histories of FDT exposure were described and compared with two other groups treated in the same institution during the 1990s: women with pregnancy-associated tumors, and premenopausal patients with no recent pregnancy or FDT exposure (controls). Women in the FDT group presented at advanced stages and with poor prognostic pathologic features as compared with controls. Their CFS and RFS rates were significantly reduced. Multivariate analysis revealed only treatment-defined tumor stages (operable, locally advanced, or metastatic) as predictive of survival rates, suggesting that survival is stage dependent. The adverse prognostic features (50% presenting with locally advanced or metastatic tumors) and poor clinical outcome with 5-year OS rate of only 44.1% were mostly notable among women diagnosed within 2 years of last FDT cycle. These findings were not explained by recent pregnancy in a further analysis. Still, tumors of women in the FDT and PABC groups shared similarities. The diagnosis of pregnancy-associated breast cancer is often reported with adverse prognostic features. Several studies, but not all, suggest prognosis is stage dependent.10–14 It is possible that certain premenopausal women are susceptible to develop breast cancer in association with FTD or pregnancy-related estrogenic stimuli, and that common tumor pathogenesis might explain similarities in tumor features in the FDT and PABC groups.

In our work, half of the FDT-exposed patients were identified soon after their diagnosis, whereas the rest were identified retrospectively. It is possible that some patients presenting during earlier years were missed and a selection bias may have existed toward patients who survived longer. Nevertheless, FDT-exposed patients, identified by both methods, presented at similar stages and shared comparable tumor features, with operable tumors occurring in 67% and 68% of these patients, respectively.

In Israel, breast cancer is far more common among Ashkenazi Jewish women (of European or American origin), compared with Sephardi Jews (of African or Asian origin) or non-Jewish (Arab) women. The adjusted incidence rates per 100,000, for the year 1997, were 96.8 for Israeli-born Jewish women, 101.1 for European- or American-born, 61 for Asian or African-born Sephardi Jewish women, and 33.5 for Arab women (Bar-Chana for the Israel Cancer Registry). Although Ashkenazi Jewish women predominated among our controls (73%), the FDT and BABC groups showed overrepresentation of Sephardi Jews and non-Jewish women. A hint of ethnic differences in susceptibility to premenopausal estrogenic stimuli is suggested. Our study design, however, cannot substantiate such a conclusion. Data from a cohort of FDT-exposed patients, with details on ethnic origin and serum sex hormone, might clarify this issue.

Several factors might affect disease occurrence in women exposed to FDT, including infertility, fertility medications, and a relatively older age at first full-term pregnancy. Infertility caused by luteal phase defects has been suggested to increase breast cancer risk in a single report,15 whereas multiple studies have failed to confirm an association between infertility and disease occurrence.8,16–25 The contribution of FDT to breast cancer development has not been demonstrated in several early case-control and cohort studies with extremely low HMG exposure rate (<5%).22,26–27 Modern series, however, with 62% to 100% HMG exposure rate showed RR of 1.6 to 2.6 and 0.8 in FTD-exposed and not exposed women, respectively (n.s. difference possibly because of sample size constraints).25,28 Women exposed to clomiphene alone might have reduced breast cancer risk possibly related to the drug’s antiestrogenic properties.29 The Australian study, which is the largest cohort, involved HMG-therapy for one or more cycles in all exposed patients (about two thirds of women in the cohort), and assessed disease occurrence in relation to time elapsed since last FDT cycle.8 This study showed an association between FDT and a transient increase in breast cancer risk. It should be noted in the Australian study, which reflects FDT use in the 1980s and early 1990s, the median number of IVF procedures was only two, whereas numerous attempts are common among modern gynecology clinics.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Breast tumors in FDT-exposed patients show aggressive features, especially when diagnosed within 2 years of an FDT cycle. Similarities were shared between tumors of FDT-exposed and PABC patients. Survival is stage dependent. Our results should be confirmed in prospective studies of FDT-exposed women, with details on ethnicity, pregnancy rates, peak serum sex hormone levels, and tumor features. Susceptibility markers have yet to be identified in women having fertility interventions.


   ACKNOWLEDGMENTS
 
ACKNOWLEDGMENTS

The acknowledgments are available online at www.annalssurgicaloncology.org.

We are indebted to the contributions from Dr. Georgeta Fried, Dr. Dorit Manor, Dr. Eitan Peer, and Dr. Avishai Sella.


   FOOTNOTES
 
Breast tumors in women with recent exposure to fertility medications, which are associated with poor prognostic features, share similarities with those of pregnancy-associated breast cancer. Survival is stage dependent.

Received for publication March 6, 2003. Accepted for publication July 15, 3003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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