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Opportunities to study the natural history of ductal carcinoma in situ are rare. A few studies of incompletely excised lesions in the premammographic era, retrospectively recognized as ductal carcinoma in situ, have demonstrated a proclivity for local recurrence in the original site. The authors report a follow-up study of 45 women with low-grade ductal carcinoma in situ treated by biopsy only, recognized retrospectively during a larger review of surgical pathology diagnoses and original histological slides for 26 539 consecutive breast biopsies performed at Vanderbilt, Baptist and St Thomas Hospitals in Nashville, TN from 1950 to 1989. Long-term follow-up was previously reported on 28 of these women. Sixteen women (36%) developed invasive breast carcinoma, all in the same breast and quadrant as their incident ductal carcinoma in situ. Eleven invasive breast carcinomas were diagnosed within 10 years of the ductal carcinoma in situ biopsy. Subsequent cases were diagnosed at 12, 23, 25, 29 and 42 years. Seven women, including one who developed invasive breast cancer 29 years after her ductal carcinoma in situ biopsy, developed distant metastasis, resulting in death 1-7 years postdiagnosis of invasive breast carcinoma. The natural history of low-grade ductal carcinoma in situ may extend more than four decades, with invasive breast cancer developing at the same site as the index lesion. This protracted natural history differs markedly from that of patients with high-grade ductal carcinoma in situ or any completely delimited ductal carcinoma in situ excised to negative margins. This study reaffirms the importance of complete margin evaluation in women treated with breast conservation for ductal carcinoma in situ as well as balancing recurrence risk with possible treatment-related morbidity for older women.

Background: Heritable risk for breast cancer includes an increasing number of common, low effect risk variants. We conducted a multistage genetic association study in a series of independent epidemiologic breast cancer study populations to identify novel breast cancer risk variants., Methods: We tested 1,162 SNPs of greatest nominal significance from stage I of the Cancer Genetic Markers of Susceptibility breast cancer study (CGEMS; 1,145 cases, 1,142 controls) for evidence of replicated association with breast cancer in the Nashville Breast Cohort (NBC; 599 cases, 1,161 controls), the Collaborative Breast Cancer Study (CBCS; 1,552 cases, 1,185 controls), and BioVU Breast Cancer Study (BioVU; 1,172 cases, 1,172 controls)., Results: Among these SNPs, a series of validated breast cancer risk variants yielded expected associations in the study populations. In addition, we observed two previously unreported loci that were significantly associated with breast cancer risk in the CGEMS, NBC, and CBCS study populations and had a consistent, although not statistically significant, risk effect in the BioVU study population. These were rs1626678 at 10q25.3 near ENO4 and KIAA1598 (meta-analysis age-adjusted OR = 1.13 [1.07-1.20], P = 5.6 × 10(-5)), and rs8046508 at 16q23.1 in the eighth intron of WWOX (meta-analysis age-adjusted OR = 1.20 [1.10-1.31], P = 3.5 × 10(-5))., Conclusions: Our data supports the association of two novel loci, at 10q25.3 and 16q23.1, with risk of breast cancer., Impact: The expanding compendium of known breast cancer genetic risk variants holds increasing power for clinical risk prediction models of breast cancer, improving upon the Gail model., (©2012 AACR)

Background: Current models of breast cancer risk prediction do not directly reflect mammary estrogen metabolism or genetic variability in exposure to carcinogenic estrogen metabolites., Methods: We developed a model that simulates the kinetic effect of genetic variants of the enzymes CYP1A1, CYP1B1, and COMT on the production of the main carcinogenic estrogen metabolite, 4-hydroxyestradiol (4-OHE(2)), expressed as area under the curve metric (4-OHE(2)-AUC). The model also incorporates phenotypic factors (age, body mass index, hormone replacement therapy, oral contraceptives, and family history), which plausibly influence estrogen metabolism and the production of 4-OHE(2). We applied the model to two independent, population-based breast cancer case-control groups, the German GENICA study (967 cases, 971 controls) and the Nashville Breast Cohort (NBC; 465 cases, 885 controls)., Results: In the GENICA study, premenopausal women at the 90th percentile of 4-OHE(2)-AUC among control subjects had a risk of breast cancer that was 2.30 times that of women at the 10th control 4-OHE(2)-AUC percentile (95% CI: 1.7-3.2, P = 2.9 × 10(-7)). This relative risk was 1.89 (95% CI: 1.5-2.4, P = 2.2 × 10(-8)) in postmenopausal women. In the NBC, this relative risk in postmenopausal women was 1.81 (95% CI: 1.3-2.6, P = 7.6 × 10(-4)), which increased to 1.83 (95% CI: 1.4-2.3, P = 9.5 × 10(-7)) when a history of proliferative breast disease was included in the model., Conclusions: The model combines genotypic and phenotypic factors involved in carcinogenic estrogen metabolite production and cumulative estrogen exposure to predict breast cancer risk., Impact: The estrogen carcinogenesis-based model has the potential to provide personalized risk estimates., (©2011 AACR)

Estrogen metabolism and growth factor signaling pathway genes play key roles in breast cancer development. We evaluated associations between breast cancer and tagging single-nucleotide polymorphisms (SNP) of 107 candidate genes of these pathways using single allele- and haplotype-based tests. We first sought concordance of associations between two study populations: the Nashville Breast Cohort (NBC; 510 cases, 988 controls), and the Cancer Genetic Markers of Susceptibility (CGEMS) breast cancer study (1,145 cases, 1,142 controls). Findings across the two study populations were concordant at tagging SNPs of six genes, and at previously published SNPs of FGFR2. We sought further replication of results for EGFR, NCOA7, and FGFR2 in the independent Collaborative Breast Cancer Study (CBCS; 1,552 cases, 1,185 controls). Associations at NCOA7 and FGFR2 replicated across all three studies. The association at NCOA7 on 6q22.32, detected by a haplotype spanning the initial protein-coding exon (5'-rs9375411, rs11967627, rs549438, rs529858, rs490361, rs17708107-3'), has not been previously reported. The haplotype had a significant inverse association with breast cancer in each study [OR(Het): 0.69 (NBC), 0.76 (CGEMS), 0.79 (CBCS)], and a meta-analysis OR(Het) of 0.75 (95% CI, 0.65-0.87, P = 1.4 × 10(-4)) in the combined study populations. The haplotype frequency was 0.07 among cases, and 0.09 among controls; homozygotes were infrequent and each OR(Hom) was not significant. NCOA7 encodes a nuclear receptor coactivator that interacts with estrogen receptor α to modulate its activity. These observations provide consistent evidence that genetic variants at the NCOA7 locus may confer a reduced risk of breast cancer.

Background: Protein phosphatase 2A (PP2A) is a major cellular phosphatase and plays key regulatory roles in growth, differentiation, and apoptosis. Women who are diagnosed with benign proliferative breast disease are at increased risk for the subsequent development of breast cancer., Methods: The authors evaluated genetic variation of PP2A holoenzyme subunits for their potential contribution to breast cancer risk. A nested case-control investigation was performed on a cohort of women who had a history of benign breast disease. The women were followed for an average of 18 years, and DNA prepared from the original archival benign breast biopsy (1954-1995) was available for 450 women who were diagnosed with breast cancer on follow-up and for 890 of 900 women in a control group who were matched on race, age, and year of entry biopsy., Results: Single allele-based and haplotype-based tests of association were conducted with assessment of significance by permutation testing. Significant risk and protective haplotypes of the PP2A structural/regulatory subunit A alpha isoform (PPP2R1A) were identified and had odds ratios of 1.63 (95% confidence interval [CI], 1.3-2.1) and 0.55 (95% CI, 0.41-0.76), respectively. These odds ratios remained significant after the analysis was adjusted for multiple comparisons. Women who had both the PPP2R1A risk haplotype and a history of proliferative breast disease had an odds ratio of 2.44 (95% CI, 1.7-3.5) for the subsequent development of breast cancer. The effects of haplotypes for 2 PP2A regulatory subunit genes, PP2 regulatory subunit B alpha isoform (PPP2R2A) and PP2A regulatory subunit B' epsilon isoform (PPP2R5E) on breast cancer risk were nominally significant but did not remain significant after the analysis was adjusted for multiple comparisons., Conclusions: The current findings supported the previously hypothesized role of PP2A as a tumor suppressor gene in breast cancer., (Copyright 2010 American Cancer Society.)

Amplification of the epithelial growth factor receptor gene ERBB2 (HER2, NEU) in breast cancer is associated with a poor clinical prognosis. In mammary gland development, this receptor plays a role in ductal and lobuloalveolar differentiation. We conducted a systematic investigation of the role of genetic variation of the ERBB2 gene in breast cancer risk in a study of 842 histologically confirmed invasive breast cancer cases and 1,108 controls from the Shanghai Breast Cancer Study. We observed that the ERBB2 gene resides within a locus of high linkage disequilibrium, composed of three major ancestral haplotypes in the study population. These haplotypes are marked by simple tandem repeat and single nucleotide polymorphisms, including the missense variants I655V and P1170A. We observed a risk-modifying effect of a highly polymorphic simple tandem repeat within an evolutionarily conserved region, 4.4 kb upstream from the ERBB2 transcription start site. Under a dominant genetic model, the age-adjusted odds ratio was 1.74 (95% confidence interval, 1.27-2.37). Its association with breast cancer, and with breast cancer stratified by histology, by histologic grade, and by stage, remained significant after correction for multiple comparisons. In contrast, we observed no association of ERBB2 single nucleotide polymorphism haplotypes with breast cancer predisposition.

Background: Mammary columnar cell lesions with atypia have been receiving increased scrutiny in view of their association with atypical hyperplasia (AH) and carcinoma. However, the few retrospective outcome studies performed have failed to establish an increased risk for recurrence or carcinoma on long-term follow-up., Methods: The authors evaluated the overall cancer risk for 1261 biopsies with columnar cell lesions (CCL) in 4569 women from the Nashville Breast Cohort who were biopsied between 1969 and 1988. On the basis of Schnitt and Vincent-Salomon's classification, they also classified 229 biopsies with CCL into 3 categories: without hyperplasia or atypia, with hyperplasia lacking atypia, and with atypia. By using a nested case-control design, they compared the risks of invasive cancer associated with these 3 categories., Results: A 2- to 3-fold increase in the occurrence of AH in the presence of CCL versus in their absence (P< .005) was observed. Relative risk of invasive breast cancer for women with both AH and CCL compared with those with AH alone did not differ significantly (risk ratio [RR]=1.55; P= .29). The presence of CCL alone was associated with a mild increase in the overall cancer risk (RR=1.47; P= .05). In the nested case-control study, no significant risk difference was observed among the 3 categories of CCL., Conclusions: The authors observed a positive association between CCL and AH. The possibility that CCL by themselves significantly elevate breast cancer risk is not well supported. However, a finding of CCL on benign breast biopsy may indicate the presence of AH, a more worrisome lesion.

Background: Atypical lobular hyperplasia (ALH) is associated with a 10% to 20% risk of subsequent invasive carcinoma, primarily in the ipsilateral breast. Nottingham grading, special tumor types, and survival after invasive cancer diagnosis were analyzed consistently for the first time., Methods: A longitudinal follow-up study of 252 women who underwent 261 benign surgical biopsies between 1950 and 1985 with a diagnosis of ALH was undertaken. Subsequent invasive breast cancers were graded and subtyped based on histologic features and the cohort assessed for cancer survival., Results: Forty-eight (19%) women developed invasive breast cancer at an average of 15.1 years. Twenty (42%) of the tumors were special subtype tumors with good prognosis. By an average of 13 years after invasive cancer diagnosis, 2 (10%) of 20 women with special type and variant tumors had died of breast cancer, compared with 9 (32%) of 28 women with tumors of no special type (24 tumors) or an unknown type (4 tumors). Only 1 patient with a tumor of low Nottingham grade died of breast cancer., Conclusions: ALH is a nonobligate cancer precursor associated with a moderate risk of breast cancer and predicts that later cancers are associated with overall excellent survival. Nearly half of the subsequent cancers show classic or variant patterns of special types with a good prognosis and the majority are of low or intermediate combined histologic grade. Treatment of women with ALH should be influenced by their modest elevation in breast cancer risk and the good prognosis and low mortality of many of these cancers., ((c) 2006 American Cancer Society.)

Background: Radial scars (RS) are benign breast lesions that have been implicated as independent risk factors for invasive breast carcinoma (IBC)., Methods: A retrospective cohort study of 9556 women who underwent biopsy between 1950-1986 and enrolled in the Nashville Breast Cohort was performed to investigate the association between RS in a benign breast biopsy and the risk of IBC. The risk associated with RS and coexistent proliferative disease (PD) was assessed adjusting for age at biopsy using a Cox hazards regression analysis with time-dependent covariates., Results: RS were identified in 880 women (9.2%). The average follow-up time was 20.4 years. Sixty-two women (7.0%) with RS developed IBC compared with 5.5% of controls. The relative risk of IBC associated with RS was 1.82 (95% confidence interval [95% CI], 1.2-2.7) at 10 years. Restricting the analysis to women age > 49 years increased the risk to 2.14 (95% CI, 0.6-2.8). These risks decreased with increasing years of follow-up. Approximately 92% of women with RS also had PD, but RS were present in only 1.3% of biopsies without PD. Analyses stratifying relative risk with regard to PD found RS to minimally elevate the relative risk of subsequent IBC., Conclusions: RS in the absence of PD is uncommon. Although the presence of RS in a benign breast biopsy mildly elevates the risk of IBC risk, the current analysis indicated that this risk can be largely attributed to the category of coexistent PD. In women with both RS and atypical hyperplasia, recommendations for interventions beyond biopsy should be based on the extent of atypical hyperplasia., (Copyright 2006 American Cancer Society.)

Adenomyoepithelioma, strictly defined, is a proliferation of both epithelial and myoepithelial elements. The broad range of lesions that may fall under this umbrella, however, may be quite diverse. The diagnostic confusion surrounding this entity and its prognostic implications have led to a diagnosis by default as malignant and to overtreatment of some patients. We evaluated available material from a series of 35 women whose slides were seen in consultation and who were diagnosed with adenomyoepithelioma or a closely related lesion. This comprehensive review of the varied histology of adenomyoepithelioma and similar lesions and their immunohistochemical properties will assist general pathologists in evaluating these sometimes difficult lesions. Follow-up and treatment information demonstrates their benignity. Architecture and histologic features should be combined with immunohistochemistry when determining categorization.

Background: Opportunities to study the natural history of ductal carcinoma in situ (DCIS) are rare. A few studies of incompletely excised lesions in the premammographic era now recognized as DCIS have provided critical insights into its proclivity for local recurrence in the original site. At the time the biopsies in the current study were originally examined, small DCIS was not diagnosed and, by default, these women were treated by biopsy only., Methods: The authors report the latest results from a follow-up study, which was published originally in 1982, of 28 women with low-grade DCIS who were treated by biopsy only. These women were from a large, prospectively identified, completely characterized cohort., Results: Eleven of 28 women developed invasive breast carcinoma (IBC), all in the same breast and quadrant from which their low-grade DCIS biopsy was taken. Seven IBCs were diagnosed within 10 years of the DCIS biopsy, 1 was diagnosed within 12 years of the DCIS biopsy, and the remaining 3 IBCs were diagnosed over 23-42 years. Five of these women, including 1 woman who developed IBC 29 years after her DCIS biopsy, developed distant metastasis, which resulted in death 1-7 years after the diagnosis of IBC., Conclusions: The natural history of low-grade DCIS can extend greater than 4 decades, with IBC developing at the same site as the previous DCIS in the majority of women. This natural history differs markedly from that of patients with high-grade DCIS and from the outcome of patients with any completely delimited DCIS excised to negative margins., (Copyright 2005 American Cancer Society.)

Estrogen is associated with many epidemiologic risk factors for invasive breast cancer. Cells that express estrogen receptors (ERs) in epithelial hyperplasia lacking atypia (EHLA) may influence breast cancer progression. We conducted a nested case-control study of 268 women with biopsy-confirmed EHLA to determine whether immunohistochemical expression of ERalpha in EHLA affects subsequent breast cancer risk. Study subjects could not have a prior or current history of breast cancer or atypical hyperplasia. Immunohistochemical stains in individual lesions and adjacent normal lobules were considered positive if >or= 10% of epithelial cells stained for ERalpha. The risk of invasive breast cancer in EHLA patients with ERalpha-positive normal lobules was twice that of other EHLA patients (95% CI = 1.0-3.8). This risk was not affected by the ERalpha status of EHLA lesions. ERalpha expression in adjacent normal lobules increases the moderate breast cancer risk previously associated with EHLA., ((c) 2004 Wiley-Liss, Inc.)

The prognostic and therapeutic implications of estrogen receptor (ER) status in breast cancer are well known. Whether ER status plays a role in benign breast lesions and the progression to malignancy has not been proven. Enlarged lobular units with columnar alteration (ELUCA), also known as unfolded lobular units, have been associated with mild elevations in subsequent breast cancer risk. We examined the association of ERalpha expression in ELUCA with invasive breast cancer risk. A nested case-control study was performed of women with ELUCA who had undergone benign breast surgery. Eighty-two women who developed invasive breast cancer on follow-up were matched by age and year of biopsy with 166 women who did not develop invasive breast cancer. Entry biopsies were stained for ERalpha (clone 6F11) without knowledge of subsequent cancer outcome. ELUCA lesions were scored as positive if greater than 10% of epithelial nuclei stained with ERalpha and at least one ELUCA contained >50% of cells staining for ERalpha. Relative risks of breast cancer were estimated by odds ratios derived from conditional logistic regression analyses. Thirty-nine percent of cases and 56% of controls had positive ERalpha staining in ELUCA. The relative risk of invasive breast cancer in women with ERalpha-negative ELUCA was 1.85 times that of women with ERalpha-positive lesions (95% confidence interval, 1.0-3.4, P=0.04). The presence of ERalpha staining in women with ELUCA is associated with a lower risk of developing subsequent invasive carcinoma. These findings have implications for risk assessment in benign breast biopsies and are of particular interest given the controversy currently surrounding hormone replacement therapy.

Aims: Loss of transforming growth factor beta type II receptor (TGFbeta-RII) expression has been associated with resistance to TGFbeta-mediated inhibition of cell proliferation and tumour progression. We investigated whether the expression of TGFbeta-RII is related to the progression of human breast cancer and whether there is a correlation between TGFbeta-RII expression and phenotypic markers of biological aggressiveness., Methods and Results: Immunohistochemical methods were used to detect TGFbeta-RII in archival breast samples including benign proliferative lesions, ductal carcinoma in situ (DCIS) and invasive mammary carcinomas (IMC). Neoplastic cells showed reduced expression of TGFbeta-RII in comparison to the normal breast tissue and benign lesions. There was a significant inverse correlation between loss of TGFbeta-RII expression and tumour grade within both DCIS (P = 0.004) and IMC (P = 0.001) groups. There was an inverse correlation between TGFbeta-RII expression and both mitotic count (P = 0.001) and clinical stage (P = 0.004). Oestrogen receptor (P = 0.07) and lymph node status (P = 0.10) were not significantly associated with TGFbeta-RII expression., Conclusions: These data indicate that decreased expression of TGFbeta-RII may contribute to breast cancer progression and is related to a more aggressive phenotype in both in-situ and invasive carcinomas.

Background: Transforming growth factors-beta (TGF-betas) regulate mammary epithelial cell division. Loss of expression of TGF-beta receptor II (TGF-beta-RII) is related to cell proliferation and tumor progression. Breast epithelial hyperplastic lesions lacking atypia (EHLA) are associated with a mild elevation in breast cancer risk. We investigated the expression of TGF-beta-RII in EHLA and the risk of subsequent invasive breast cancer., Methods: We conducted a nested case-control study of women with biopsy-confirmed EHLA who did not have a history of breast cancer or atypical hyperplasia of the breast. Case patients (n = 54) who subsequently developed invasive breast cancer were matched with control patients (n = 115) who did not. Formalin-fixed, paraffin-embedded sections of breast biopsy specimens of all 169 patients with EHLA were studied by immunohistochemical analysis with antibodies against TGF-beta-RII. All P values are two-sided., Results: Women with breast EHLA and 25%-75% TGF-beta-RII-positive cells or less than 25% TGF-beta-RII-positive cells had odds ratios of invasive breast cancer of 1.98 (95% confidence interval [CI] = 0.95-4.1) or 3.41 (95% CI = 1.2-10.0), respectively (P for trend =.008). These risks are calculated with respect to women with EHLA that had greater than 75% TGF-beta-RII expression. Women with a heterogeneous pattern of TGF-beta-RII expression in their normal breast lobular units and either greater than 75%, 25%-75%, or less than 25% positive cells in their EHLA had odds ratios for breast cancer risk of 0.742 (95% CI = 0.3-1.8), 2.85 (95% CI = 1.1-7.1), or 3.55 (95% CI = 1.0-10.0), respectively (P for trend =.003). These risks are relative to women with a homogeneous pattern of expression in their normal lobular units and greater than 75% positive cells in their EHLA., Conclusion: This study indicates that loss of TGF-beta-RII expression in epithelial cells of EHLA is associated with increased risk of invasive breast cancer.

Background: Little information is available regarding the invasive breast carcinoma risk associated with estrogen replacement therapy (ERT) in women with histories of histologically defined breast lesions., Methods: A retrospective cohort study of a consecutive series of women who underwent breast biopsies that proved to be benign between 1952-1978 was conducted. Follow-up data were obtained for 9494 women (87.6% of women eligible for follow-up). To investigate the effect of ERT on invasive breast carcinoma risk, the analysis was restricted to women with premenopausal breast disease whose follow-up extended through menopause and who did not develop premenopausal breast carcinoma. Relative risks were calculated with respect to women who took ERT but whose benign breast biopsies had neither atypical hyperplasia (AH), complex fibroadenoma (CFA), nor proliferative disease without atypia (PDWA)., Results: During 190,845 woman-years of follow-up there were 444 confirmed cases of invasive breast carcinoma in the entire cohort. Women with a history of AH had relative risks of invasive breast carcinoma of 2.87 (95% confidence interval [95% CI], 1.3-6.3) and 2.53 (95% CI, 1.0-6.3) if they did or did not take ERT, respectively. For women with a history of CFA these risks were 1.57 (95% CI, 0.72-3.4) and 1.46 (95% CI, 0.53-4.0), respectively, whereas for women with a history of PDWA they were 1.37 (95% CI, 0.88-2.1) and 1.13 (95% CI, 0.69-1.9), respectively., Conclusions: ERT does not significantly elevate the risk of invasive breast carcinoma in women with previous histologically defined benign breast disease. Therefore, ERT is not contraindicated in these women.

Background: The stratification of ductal carcinoma in situ (DCIS) of the human breast into prognostically relevant categories by size and histologic pattern is a current concern. Few studies have been able to follow women after the identification of any type of DCIS when they have had biopsy only., Methods: This is an extension of a follow-up study of a group of 28 women with small, noncomedo ductal carcinomas in situ that were excised by biopsy only, published in 1982. All these women have now been successfully followed for an average of almost 30 years., Results: The overall risk of development of invasive carcinoma for these women over almost 30 years is nine times that of the general population (95% confidence interval, 4.7-17). This is similar to the 11-fold elevation in relative risk that was determined after about 15 years of follow-up. All invasive carcinomas have developed in the same area in the same breast. There were two women in whom invasive carcinoma developed between 20 and 30 years after initial biopsy. One other woman had an extensive noncomedo DCIS that was identified 25 years after her initial biopsy, but had no evidence of invasive disease., Conclusions: The natural history of small, noncomedo DCIS can last over at least 2 decades, with invasive carcinoma developing at the same site in which DCIS was previously discovered in a significant percentage of women (broadly, between 25%-50%). This is quite different from the natural history of comedo DCIS or any type of DCIS treated purposefully by surgery alone.

Background: Fibroadenomas are benign breast tumors that are commonly diagnosed in young women and are associated with a slight increase in the risk of breast cancer. These lesions vary considerably in their histologic characteristics. We assessed the correlation between the histologic features of fibroadenomas and the risk of subsequent breast cancer., Methods: We conducted a retrospective cohort study of a consecutive series of patients with fibroadenoma diagnosed between 1950 and 1968. Follow-up data were obtained for 1835 patients (90 percent of those eligible). Fibroadenomas with cysts, sclerosing adenosis, epithelial calcifications, or papillary apocrine changes were classified as complex. The rate of subsequent breast cancer among the patients was compared with the rates in two control groups, women listed in the Connecticut Tumor Registry and women chosen from among the patients' sisters-in-law., Results: The risk of invasive breast cancer was 2.17 times higher among the patients with fibroadenoma than among the controls (95 percent confidence interval, 1.5 to 3.2). The relative risk increased to 3.10 among patients with complex fibroadenomas (95 percent confidence interval, 1.9 to 5.1) and remained elevated for decades after diagnosis. Patients with benign proliferative disease in the parenchyma adjacent to the fibroadenoma had a relative risk of 3.88 (95 percent confidence interval, 2.1 to 7.3). Patients with a family history of breast cancer in whom complex fibroadenoma was diagnosed had a relative risk of 3.72, as compared with controls with a family history (95 percent confidence interval, 1.4 to 10). Two thirds of the patients had noncomplex fibroadenomas and no family history of breast cancer and did not have an increased risk., Conclusions: Fibroadenoma is a long-term risk factor for breast cancer. The risk is increased in women with complex fibroadenomas, proliferative disease, or a family history of breast cancer.

Background: Women with proliferative breast disease (PD) have been observed to have an increased risk of breast cancer. The authors evaluated the effect of PD on breast cancer risk in a case-control study among participants of the Breast Cancer Detection Demonstration Project (BCDDP)., Methods: More than 280,000 women were screened in the BCDDP at 29 centers. Study subjects were selected from BCDDP participants who underwent biopsy that revealed benign breast tissue. There were five BCDDP centers for which histologic slides were available on more than 85% of the benign biopsy specimens. Case patients for this study were the 95 women from these five centers who had breast cancer develop during follow-up. Two matched control patients who did not have breast cancer develop were selected for each case. The biopsy slides were reviewed by two pathologists who were blinded with regard to cancer outcome., Results: Women with atypical hyperplasia (AH) had 4.3 times the breast cancer risk of women without PD (95% confidence interval [CI], 1.7-11). In women with PD lacking AH, the relative risk was 1.3 (95% CI, 0.77-2.2). A family history of breast cancer (FH) increased breast cancer risk 2.4 times (95% CI, 1.4-4.3). The joint occurrence of FH and AH had a strong synergistic effect on breast cancer risk., Conclusions: AH is a reliable marker of increased breast cancer risk among women undergoing breast biopsy.