Affiliations of authors: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Building, Baltimore, MD.
Correspondence to: Nancy E. Davidson, MD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Room 409, Baltimore, MD 21231-1000 (e-mail: davidna{at}jhmi.edu)
Women with early-stage breast cancer face three late breast cancer consequences: disease recurrence within the conserved breast, development of a contralateral breast cancer, and manifestation of distant metastases. Although local therapy with surgery and radiotherapy is used to minimize the first possibility, adjuvant systemic therapy may theoretically reduce the likelihood of all three events. In the absence of locoregional or distant metastases, a contralateral breast cancer in a breast cancer survivor is generally regarded as a new cancer rather than a manifestation of disease recurrence. Several small studies have suggested that a woman's second breast cancer is likely to resemble her first breast cancer. This seems plausible because both cancers arise in a woman with the same genetic, hormonal, and environmental exposures. In this issue of the Journal, Swain et al. (1) suggest that the characteristics of the first breast cancer may indeed predict the features of the second breast cancer and that the use of tamoxifen may perturb this balance. These data, if confirmed, may have important implications for our understanding of tumor initiation and progression and our consideration of treatment and prevention strategies.
Swain and her colleagues (1) present a combined retrospective analysis of the histology and estrogen receptor alpha (ER) and progesterone receptor (PR) status of the primary and subsequent contralateral invasive breast cancer in women enrolled in three National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials investigating questions of chemotherapy dose and schedule (24). All patients received doxorubicincyclophosphamide-based chemotherapy; and importantly, no statistically significant difference in disease-free or overall survival was observed between any of the arms in the three studies, B-18, B-22, and B-25 (24). Regardless of hormone receptor status, tamoxifen was routinely prescribed to women aged 50 years or older and was not prescribed to women aged younger than 50 years. This study design permitted Swain et al. (1) to compare the hormone receptor status in the contralateral breast cancer to that of the initial breast cancer in four groups of women: women with ER-positive tumors who received tamoxifen, women with ER-negative tumors who received tamoxifen, women with ER-positive tumors who did not receive tamoxifen, and women with ER-negative tumors who did not receive tamoxifen. Not surprisingly, given the nature of the chemotherapy questions under study in the three trials, 56% of the patients in the analysis by Swain et al. (1) were younger than 50 years of age, limiting our ability to extrapolate the results to older women.
Of 5513 evaluable patients, 176 (3%) developed a contralateral breast cancer at a median of 4.5 years after study enrollment (1). Comparison of ER status could only be performed for 110 tumor pairs because of unknown ER status of the ipsilateral and/or contralateral breast cancer (n = 28) or non-invasive disease (n = 38). A high concordance rate between the ER status of the initial primary cancer and subsequent contralateral breast cancer was reported for the 62 women who did not receive tamoxifen (observed odds ratio [OR] of the association between ER of the primary and contralateral breast cancer = 14.8, P<.001). By contrast, the concordance between the ER status of the primary cancer and the contralateral breast cancer was not statistically significant for the 48 women who received tamoxifen (OR = 3.4, P = .25). Swain et al. (1) suggested that the lack of association between ER status of the primary cancer and contralateral breast cancer in women who received tamoxifen reflects the ability of tamoxifen to reduce the incidence of ER-positive but not ER-negative tumors. An alternative explanation is that the lack of association could reflect a lack of statistical power, given the smaller number of women in the second group.
Several other factors must be considered when evaluating the results of the study by Swain et al. (1). First, it is important to recall that all patients in their study received chemotherapy. Results from the 1995 Oxford meta-analysis (5) suggest that polychemotherapy is associated with a 20% reduction in incidence of contralateral breast cancer independent of tamoxifen. Based on the emerging data regarding increased efficacy of chemotherapy in women with ER-negative versus ER-positive breast cancer (68), it is conceivable that chemotherapy could have altered both the incidence and the phenotype of the contralateral breast cancer observed in the study by Swain et al. (1). Second, tamoxifen was prescribed concurrently with chemotherapy in two of the NSABP trials (3,4). It has been suggested that concurrent administration of tamoxifen and chemotherapy is less beneficial than the sequential administration of the two modalities (9). Whether the sequential administration of chemotherapy and tamoxifen would have a different influence on contralateral breast cancer is simply not known. Third, many of the young patients in the analysis by Swain et al. (1) who did not receive tamoxifen by design may have received endocrine therapy in the form of chemotherapy-induced ovarian suppression or ablation; whether this would affect the incidence or characteristics of contralateral breast cancer is not known. Finally, 22% of contralateral breast cancer reported in the NSABP B-18, B-22, and B-25 trials were non-invasive and were excluded from analysis by Swain et al. (1). A recent study demonstrated that the ER status of ductal carcinoma in situ (DCIS) is predictive of the patient response to tamoxifen (10). In the NSABP B-24 trial (11) and in a study by the DCIS Working Party (12), tamoxifen reduced the incidence of contralateral breast cancer. In the NSABP B-24 trial, tamoxifen reduced the incidence of both ipsilateral and contralateral breast cancer (11), but such a benefit was not observed in the small cohort of women with ER-negative DCIS (10). It would be informative to evaluate the ER status of the non-invasive contralateral breast cancer in the study by Swain et al. because this could increase the number of contralateral breast cancer available for analysis and may also provide insight into breast cancer progression.
How do the findings by Swain et al. (1) compare with our understanding from other studies? Several small retrospective investigations suggested that ER status of primary and synchronous or metachronous contralateral breast cancer was generally concordant, regardless of intervening treatment. By contrast, the Baylor Breast Center (13) evaluated 177 patients identified from a tissue bank for whom ER and PR status were available for both the initial and the contralateral breast cancer. Of 114 women who did not receive any adjuvant systemic therapy, more than 80% of the women developed an ER-positive contralateral breast cancer regardless of the ER status of the first primary, suggesting that there was no correlation between the ER status of the original tumor and that of the contralateral breast cancer in the absence of therapy (13). In 34 women who received tamoxifen with or without chemotherapy, 50% of the contralateral breast cancers were ER-positive and 50% were ER-negative. By comparison with the study by Swain et al. (1), the Baylor Breast Center study (13) has the advantage of including women who received no adjuvant therapy, affording us a snapshot of the natural history of the cancer. However, the Baylor Breast Center study (13) has the disadvantage of using a retrospectively identified population with uncertain biases. It is also notable that the median age at diagnosis of primary breast cancer in the Baylor Breast Center study (13) was 62 years compared with a median age at diagnosis of 48 years in the study by Swain et al. (1). One explanation for the difference between the two studies may be that the proportion of primary tumors that express ER increases with age.
In addition to the study by Swain et al. (1), a number of studies support the idea that tamoxifen or raloxifene can affect the phenotype of a contralateral breast cancer. Indeed a meta-analysis of the tamoxifen prevention trials demonstrated a statistically significant 48% reduction in the incidence of ER-positive but not ER-negative breast cancer (14). Similarly a reduction in the incidence of ER-positive but not ER-negative breast cancer was reported in a randomized trial of raloxifene for postmenopausal women with osteoporosis (15). These findings suggest that selective estrogen receptor modulators can interfere with breast cancer initiation and/or progression. Emerging data suggest that aromatase inhibitors administered instead of or after tamoxifen are associated with a substantial reduction in the incidence of contralateral breast cancer (16,17). It will be of interest to evaluate the hormone receptor status of contralateral breast cancers that develop in women taking aromatase inhibitors.
In addition, several treatment trials (1820) indirectly support the hypothesis that specific characteristics of the first breast cancer predict features of the contralateral breast cancer. Rutqvist et al. (18) reported that, in a randomized trial comparing adjuvant tamoxifen therapy for 2 or 5 years with no therapy, women who received tamoxifen had a statistically significantly lower incidence of contralateral breast cancer and a lower incidence of ER-positive contralateral breast cancer than women who received no therapy. A trial of adjuvant chemotherapy with or without tamoxifen for women with lymph node-negative ER-negative breast cancer, NSABP B-23, failed to demonstrate any benefit of tamoxifen on contralateral breast cancer incidence (19). Finally, Intergroup Trial 0102 (20) showed an advantage for tamoxifen only for women with ER-positive breast cancer. The results of these three studies (1820) are concordant with those reported by Swain et al. (1).
If confirmed, these data (1) have important implications for recommendations about treatment and risk reduction strategies. They give further credence to the goal of individualized strategies that consider attributes of the tumor and the patient. If a woman is at risk for a second breast cancer that is biologically similar to her first cancer, then effective adjuvant systemic therapy may also provide secondary prevention for the contralateral breast. Moreover, the contralateral breast may be regarded as "high risk" and represent a model for investigating new adjuvant and prevention approaches. Finally, Swain and colleagues (1) could only examine hormone receptor status and histology of primary and contralateral breast cancer. Initial microarray studies suggest that breast cancer may consist of several distinct molecular profiles (21,22). In the future, new technologies that permit comparison of multiple gene transcripts or proteins should provide more comprehensive insight into the biology of breast cancer, allowing us to ascertain whether the development of contralateral breast cancer is indeed "déjà vu all over again" (23).
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