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Breast Cancer Risk by Extent and Type of Atypical Hyperplasia: An Update From the Nurses' Health Studies
EPIDEMIOLOGY Breast Cancer Risk by Extent and Type of Atypical Hyperplasia: An Update From the Nurses’ Health Studies Collins LC, Aroner SA, Connolly JL, et al (Harvard Med School, Boston, MA; Harvard T. H. Chan School of Public Health, Boston, MA; et al) Cancer 122:515-520, 2016
Background.dWomen with atypical hyperplasia (AH) on a benign breast biopsy specimen are at increased risk for the development of breast cancer. However, the relation between the type and extent of AH (atypical ductal hyperplasia [ADH] vs atypical lobular hyperplasia [ALH]) and the magnitude of the breast cancer risk is not well defined. Methods.dA nested case-control study of benign breast disease and breast cancer risk was conducted. Women with breast cancer and prior benign breast biopsy findings (488 cases) were matched to women with prior benign breast biopsy findings who were free from breast cancer (1907 controls). Benign breast biopsy slides were reviewed and categorized as nonproliferative, proliferative without atypia, or AH (ADH or ALH). The number of foci of AH was also recorded. Results.dAmong women with ADH, the interrelation between the extent of atypia and breast cancer risk was not significant (odds ratio [OR] for 1 or 2 foci, 3.5; 95% confidence interval [CI], 2.2-5.6; OR for $3 foci, 2.7; 95% CI, 1.4-5.1; P ¼ .41). Similarly, although the risk with ALH was higher for those with $3 foci than for those with <3 foci, the difference was
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not statistically significant (OR for 1 or 2 foci, 5.2; 95% CI, 2.7-10.0; OR for $3 foci, 8.0; 95% CI, 4.5-14.2; P ¼ .19). Conclusions.dThis analysis demonstrates that the extent of ADH or ALH does not significantly contribute to breast cancer risk. The lack of a significant dose-response relation between the extent and type of atypia and breast cancer risk suggests that it would be premature to use the extent of atypia to influence management decisions for women with ADH or ALH. This study by Collins and colleagues attempts to clarify the level of risk associated with AH identified on breast biopsies by assessing the subsequent development of breast cancer according to both the type and extent of AH. This nested case-control study examined medical records and pathology results from women followed in the Nurses’ Health Study with a history of benign breast disease (BBD). Women who developed breast cancer after a diagnosis of BBD were matched against controls who were free of breast cancer but had biopsyproven BBD. The researchers stratified the BBD as non-proliferative, proliferative without atypia, or AH, either ADH or ALH. They also noted the number of foci involved by AH. The 1.6-fold increase in breast cancer risk associated with proliferative breast disease without atypia in this study is consistent with prior research. The presence of AH conferred a substantial, 4.5-fold increase in breast cancer risk compared with a lack of proliferative breast disease, again consistent with prior reports.
Breast Diseases: A Year BookÒ Quarterly Vol 27 No 4 2017
Upon review by type of AH, a higher level of risk was seen in women with ALH (OR, 6.6; 95% CI, 4.2-10.3) or a combination of ALH and ADH (OR 6.7; 95% CI, 3.2-13.9) compared with women who had ADH (OR 3.2; 95% CI, 2.1-4.7). This finding contrasts with data from the Mayo Clinic Benign Breast Disease Cohort, which did not show a difference in breast cancer risk by type of AH (relative risk for ALH vs ADH, 4.8 vs 3.9, respectively; P ¼.54),1 but aligns with a meta-analysis by Zhou and colleagues2 that showed that women with ALH have a higher risk of breast cancer (OR 5.14; 95% CI, 3.5-75) than women with ADH (OR 2.9; 95% CI, 2.2-4.0). In the present study, the extent of AH, as measured by the number of foci, did not appear to alter the risk for breast cancer in women with AH. Although there was a higher risk for subsequent breast cancers in women with 3 or more foci of ALH compared with 1 or 2 foci, this finding was not statistically significant (OR for 1 or 2 foci, 5.2; 95% CI, 2.7-10.0; OR for $3 foci, 8.0; 95% CI, 4.5-14.2; P ¼.19). This contrasts with more recent findings reported by Degnim and colleagues3 in which risk increased with an increasing number of foci for both ADH and ALH (for 1, 2, and 3 foci, relative risks were 2.65, 5.19, and 8.94, respectively, for ADH [P < .001] and 2.58, 3.49, and 4.97, respectively, for ALH [P ¼.001]). These findings go against the hypothesis proposed by Collins and colleagues that the risk of ALH is obscuring the breast cancer risk related to the extent of the AH.
The present study included 488 women with a history of BBD findings and a history of breast cancer diagnosed between 1976 and 1998, based on self-reports and a review of past medical records. The cases were matched against 1907 controls with BBD but without breast cancer. A strength of this study is that the researchers obtained the prior pathology slides for both cases and controls. The pathology slides were reviewed by 1 of 3 pathologists. A second pathologist reviewed the slide when AH was identified. The number of foci involved and whether the hyperplasia was ALH or ADH were also determined when AH was identified. This review of prior biopsies, some dating back 40 years, helped control for the differences in experiences of the original pathologists, who worked in multiple settings over a period of more than 20 years, to identify AH consistently. These findings are of clinical interest, as they examine a fairly common biopsy result that, while not a malignancy, cannot be described as completely benign breast tissue. The significance of AH can be difficult to convey to women. It has been well
established that AH confers an increased risk for breast cancer. The extent of AH has been thought to alter the level of risk for subsequent breast cancer; however, the authors of this study did not find an association between the extent of AH (as measured by the number of foci) and the risk for subsequent breast cancer. The Breast Cancer Prevention Trial4 showed an 86% reduction in breast cancer risk with the use of tamoxifen by women with AH; these findings were not further evaluated by the type or extent of hyperplasia. Nonetheless, substantial benefits in this high-risk population have been showed. Preventive therapy with selective estrogen re-uptake modulators or aromatase inhibitors is notoriously underutilized,5 perhaps because women or their clinicians underestimate their risk of breast cancer and the benefits of preventive therapy, particularly in women with AH. This study provides further data on breast cancer risk to support that women with AH are an ideal population to target for preventive therapy. S. Day, APRN, BC, FNP T. B. Bevers, MD
References 1. Hartmann LC, Radisky DC, Frost MH, et al. Understanding the premalignant potential of atypical hyperplasia through its natural history: a longitudinal cohort study. Cancer Prev Res (Phila). 2014;7: 211-217. 2. Zhou WB, Xue DQ, Liu XA, Ding Q, Wang S. The influence of family history and histological stratification on breast cancer risk in women with benign breast disease: a metaanalysis. J Cancer Res Clin Oncol. 2011;137:1053-1060. 3. Degnim AC, Dupont WD, Radisky DC, et al. Extent of atypical hyperplasia stratifies breast cancer risk in 2 independent cohorts of women. Cancer. 2016;122: 2971-2978. 4. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388. 5. Waters EA, McNeel TS, Stevens WM, Freeman AN. Use of tamoxifen and raloxifene for breast cancer chemoprevention in 2010. Breast Cancer Res Treat. 2012;134: 875-880.
Breast Diseases: A Year BookÒ Quarterly Vol 27 No 4 2017
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Background.dWomen with atypical hyperplasia (AH) on a benign breast biopsy specimen are at increased risk for the development of breast cancer. However, the relation between the type and extent of AH (atypical ductal hyperplasia [ADH] vs atypical lobular hyperplasia [ALH]) and the magnitude of the breast cancer risk is not well defined. Methods.dA nested case-control study of benign breast disease and breast cancer risk was conducted. Women with breast cancer and prior benign breast biopsy findings (488 cases) were matched to women with prior benign breast biopsy findings who were free from breast cancer (1907 controls). Benign breast biopsy slides were reviewed and categorized as nonproliferative, proliferative without atypia, or AH (ADH or ALH). The number of foci of AH was also recorded. Results.dAmong women with ADH, the interrelation between the extent of atypia and breast cancer risk was not significant (odds ratio [OR] for 1 or 2 foci, 3.5; 95% confidence interval [CI], 2.2-5.6; OR for $3 foci, 2.7; 95% CI, 1.4-5.1; P ¼ .41). Similarly, although the risk with ALH was higher for those with $3 foci than for those with <3 foci, the difference was
264
not statistically significant (OR for 1 or 2 foci, 5.2; 95% CI, 2.7-10.0; OR for $3 foci, 8.0; 95% CI, 4.5-14.2; P ¼ .19). Conclusions.dThis analysis demonstrates that the extent of ADH or ALH does not significantly contribute to breast cancer risk. The lack of a significant dose-response relation between the extent and type of atypia and breast cancer risk suggests that it would be premature to use the extent of atypia to influence management decisions for women with ADH or ALH. This study by Collins and colleagues attempts to clarify the level of risk associated with AH identified on breast biopsies by assessing the subsequent development of breast cancer according to both the type and extent of AH. This nested case-control study examined medical records and pathology results from women followed in the Nurses’ Health Study with a history of benign breast disease (BBD). Women who developed breast cancer after a diagnosis of BBD were matched against controls who were free of breast cancer but had biopsyproven BBD. The researchers stratified the BBD as non-proliferative, proliferative without atypia, or AH, either ADH or ALH. They also noted the number of foci involved by AH. The 1.6-fold increase in breast cancer risk associated with proliferative breast disease without atypia in this study is consistent with prior research. The presence of AH conferred a substantial, 4.5-fold increase in breast cancer risk compared with a lack of proliferative breast disease, again consistent with prior reports.
Breast Diseases: A Year BookÒ Quarterly Vol 27 No 4 2017
Upon review by type of AH, a higher level of risk was seen in women with ALH (OR, 6.6; 95% CI, 4.2-10.3) or a combination of ALH and ADH (OR 6.7; 95% CI, 3.2-13.9) compared with women who had ADH (OR 3.2; 95% CI, 2.1-4.7). This finding contrasts with data from the Mayo Clinic Benign Breast Disease Cohort, which did not show a difference in breast cancer risk by type of AH (relative risk for ALH vs ADH, 4.8 vs 3.9, respectively; P ¼.54),1 but aligns with a meta-analysis by Zhou and colleagues2 that showed that women with ALH have a higher risk of breast cancer (OR 5.14; 95% CI, 3.5-75) than women with ADH (OR 2.9; 95% CI, 2.2-4.0). In the present study, the extent of AH, as measured by the number of foci, did not appear to alter the risk for breast cancer in women with AH. Although there was a higher risk for subsequent breast cancers in women with 3 or more foci of ALH compared with 1 or 2 foci, this finding was not statistically significant (OR for 1 or 2 foci, 5.2; 95% CI, 2.7-10.0; OR for $3 foci, 8.0; 95% CI, 4.5-14.2; P ¼.19). This contrasts with more recent findings reported by Degnim and colleagues3 in which risk increased with an increasing number of foci for both ADH and ALH (for 1, 2, and 3 foci, relative risks were 2.65, 5.19, and 8.94, respectively, for ADH [P < .001] and 2.58, 3.49, and 4.97, respectively, for ALH [P ¼.001]). These findings go against the hypothesis proposed by Collins and colleagues that the risk of ALH is obscuring the breast cancer risk related to the extent of the AH.
The present study included 488 women with a history of BBD findings and a history of breast cancer diagnosed between 1976 and 1998, based on self-reports and a review of past medical records. The cases were matched against 1907 controls with BBD but without breast cancer. A strength of this study is that the researchers obtained the prior pathology slides for both cases and controls. The pathology slides were reviewed by 1 of 3 pathologists. A second pathologist reviewed the slide when AH was identified. The number of foci involved and whether the hyperplasia was ALH or ADH were also determined when AH was identified. This review of prior biopsies, some dating back 40 years, helped control for the differences in experiences of the original pathologists, who worked in multiple settings over a period of more than 20 years, to identify AH consistently. These findings are of clinical interest, as they examine a fairly common biopsy result that, while not a malignancy, cannot be described as completely benign breast tissue. The significance of AH can be difficult to convey to women. It has been well
established that AH confers an increased risk for breast cancer. The extent of AH has been thought to alter the level of risk for subsequent breast cancer; however, the authors of this study did not find an association between the extent of AH (as measured by the number of foci) and the risk for subsequent breast cancer. The Breast Cancer Prevention Trial4 showed an 86% reduction in breast cancer risk with the use of tamoxifen by women with AH; these findings were not further evaluated by the type or extent of hyperplasia. Nonetheless, substantial benefits in this high-risk population have been showed. Preventive therapy with selective estrogen re-uptake modulators or aromatase inhibitors is notoriously underutilized,5 perhaps because women or their clinicians underestimate their risk of breast cancer and the benefits of preventive therapy, particularly in women with AH. This study provides further data on breast cancer risk to support that women with AH are an ideal population to target for preventive therapy. S. Day, APRN, BC, FNP T. B. Bevers, MD
References 1. Hartmann LC, Radisky DC, Frost MH, et al. Understanding the premalignant potential of atypical hyperplasia through its natural history: a longitudinal cohort study. Cancer Prev Res (Phila). 2014;7: 211-217. 2. Zhou WB, Xue DQ, Liu XA, Ding Q, Wang S. The influence of family history and histological stratification on breast cancer risk in women with benign breast disease: a metaanalysis. J Cancer Res Clin Oncol. 2011;137:1053-1060. 3. Degnim AC, Dupont WD, Radisky DC, et al. Extent of atypical hyperplasia stratifies breast cancer risk in 2 independent cohorts of women. Cancer. 2016;122: 2971-2978. 4. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371-1388. 5. Waters EA, McNeel TS, Stevens WM, Freeman AN. Use of tamoxifen and raloxifene for breast cancer chemoprevention in 2010. Breast Cancer Res Treat. 2012;134: 875-880.
Breast Diseases: A Year BookÒ Quarterly Vol 27 No 4 2017
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