Ghosh, K

Abstract Introduction: Smoking is a risk factor for poor outcomes following breast reconstructive surgery, including wound dehiscence and infection. Women who would choose to have reconstructive surgery after mastectomy for breast cancer are unable to do so if they have not quit smoking. The specific aims of this project are to 1) design and implement an intervention to assist these patients in quitting and 2) evaluate its efficacy. Methods: Baseline data regarding current practices was collected via a chart review of 75 smoking breast cancer surgery patients from 1/1/2012-12/31/13. Charts were analyzed for documentation of smoking status, quit advice, resources provided and used, and smoking status at follow-up. Formative research informed the design of an Ask-Advise-Refer intervention for all new breast cancer patients seen at Mayo Clinic. Intervention Design: Smoking patients were identified prior to their initial Breast Cancer evaluation at Mayo Clinic, Rochester, during a standard intake call. Smoking status was documented by the rooming assistant to alert the physicians of smoking status, and physicians asked these patients about their smoking behavior, discussed the risks of smoking both for surgical procedures and breast cancer, and offered a Nicotine Dependence Consultation with a tobacco treatment specialist in an “opt-out” strategy that emphasized the importance of smoking cessation as part of the breast cancer treatment process. The advice and referral was documented in the medical record. Evaluation of the intervention was performed via a chart review of patients seen after one year of implementation. Intervention Evaluation Results: Breast clinic physicians documented smoking status in all patients seen after implementation. Referral to the Nicotine Dependence Center for cessation counseling increased from 29% (22/75) to 74% (20/27). Among those referred, attendance at the consultation increased from 41% (9/22) to 75% (15/20), suggesting stronger provider encouragement of cessation services. 30-day abstinence rates for those who attended a consult prior to 5/1/16 were 46% (6/13), which is consistent with baseline data. Conclusions: An Ask-Advise-Refer intervention for new breast cancer patients seen at Mayo Clinic, Rochester, who report current smoking, has been associated with higher rates of provider counseling on tobacco dependence, referral to available services, and patient attendance at referrals. Attending a referral greatly increases a patient's chances of quitting smoking for at least 30 days compared to average spontaneous quit rates in this population. This model is low-cost, time-efficient for providers, and applicable to most practice settings. Finding ways to make this intervention self-sustaining and applicable to multiple other practices could greatly improve our patient's health outcomes. Citation Format: Nolan M, Ghosh K, Warner DO. Design, implementation and evaluation of a smoking cessation intervention for patients undergoing breast cancer surgery [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-17-02.

Abstract This abstract was not presented at the symposium.

Abstract Background Women with benign breast disease (BBD) have an increased risk for breast cancer (BC). Almost 30% of all BCs develop in women with prior BBD. Information about the features of the expected BCs after BBD would enable individualized surveillance and prevention strategies for these women. We sought to characterize BCs developing in a large cohort of women with BBD. Methods Our cohort includes 13,485 women who underwent breast biopsy for mammographic or palpable concern between 1967-2001. Biopsy slides were reviewed and classified as nonproliferative (NP), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH). BCs were identified by follow-up questionnaires, medical records, and Tumor Registry data. BC tissues were obtained and reviewed. Results With a median follow-up of 15.8 years, 1273 women developed BC. Most BCs were invasive (81%), among which 61% were ductal, 13% mixed ductal/lobular, and 14% lobular. Two thirds were intermediate or high-grade, and 29% were node positive. Cancer characteristics were similar across the three histologic categories of BBD, with similar frequency of DCIS and invasive disease, tumor size, time to invasive BC, histologic type of BC, nodal positivity and HER2 positivity. Women with AH had a higher frequency of ER+ BC (91%) vs women with PD (80%) or NP (85%), p=0.02. Conclusion A substantial proportion of all BCs develop in women with prior BBD. We show that the majority of BCs after BBD are invasive tumors of ductal type, with a substantial proportion node positive. 84% of cancers were ER-positive. Chemoprevention should be strongly encouraged in higher-risk women with BBD. Citation Format: Visscher DW, Frost MH, Hartmanan LC, Frank RD, Vierkant RA, McCullough AE, Winham SJ, Vachon C, Ghosh K, Brandt KR, Farrell AM, Tarabishy Y, Hieken TJ, Haddad TC, Kraft RA, Radisky DC, Degnim AC. Clinicopathologic features of breast cancers that develop in women with previous benign breast disease. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-10-19.

Abstract Background Women with atypical hyperplasia (AH) are at an approximately four-fold increased risk of subsequent breast cancer (BC). Mammographic breast density (MBD) is a well-established risk factor for BC, but its contribution to BC risk in women with AH remains an open question. We previously reported no association between MBD [measured by Wolfe's parenchymal pattern (PP)] and BC risk in a cohort of 147 women with AH. Here, we present results in an expanded cohort of 459 women diagnosed with AH between 1985 and 2001. Methods The Mayo Clinic Benign Breast Disease Cohort includes 13,485 women who had benign core and/or excisional biopsy 1967-2001. Biopsy tissues were reviewed by our study pathologist to determine presence of AH. MBD was available from clinical records starting in 1985, coded as PP (the standard for 1985-1996) or BI-RADS (1997-2001) density criteria. The original four-level PP (N1-fatty, P1-ductal prominence <25% of breast, P2-ductal prominence >25%, DY-dysplasia) and BI-RADS (fatty, scattered densities, heterogeneously dense, extremely dense) measures were re-categorized as low, moderate or high MBD by combining the middle two categories for each. BC events and clinical information were obtained by questionnaires, medical records and the Mayo Clinic Tumor Registry. Women were followed from benign biopsy to date of BC, death or last contact. Standardized incidence ratios (SIRs) were generated overall and within subgroups defined by density measure (PP vs. BI-RADS), number of atypical foci, and BMI by dividing the observed number of BCs by population-based expected values. Cox regression was used to estimate MBD hazard ratios after adjustment for demographic and clinical variables. Results Of the 551 women diagnosed with AH between 1985 and 2001, 459 (83%) had MBD data within 1 year prior to biopsy. Of these, 68 (15%) had low, 221 (48%) had moderate, and 170 (37%) had high MBD, respectively. Over a median follow-up of 11.7 years, 80 BCs were observed. SIRs for breast cancer did not differ significantly across density categories, overall or within any subgroups examined (see Table). Cox regression adjusting for age, BMI and density measure (PP vs. BI-RADS) also failed to identify an association with MBD (p=0.55). Low MBDModerate MBDHigh MBD N / BCsSIR (95% CI)N / BCsSIR (95% CI)N / BCsSIR (95% CI)P-valueOverall68/123.5 (1.8,6.1)221/393.6 (2.5,4.9)170/293.4 (2.3,4.8)0.97MBD Measure PP59/113.6 (1.8,6.5)85/153.0 (1.7,5.0)130/243.3 (2.2,5.0)0.87BI-RADS9/12.7 (0.1,14.7)136/244.0 (2.6,6.0)40/53.4 (1.1,7.9)0.90No. Atypical Foci 147/62.3 (0.9,5.1)123/182.8 (1.7,4.4)96/163.5 (2.0,5.8)0.63214/47.5 (2.0,19.1)58/134.8 (2.6,8.3)41/62.5 (0.9,5.5)0.213+7/26.7 (0.8,24.0)40/84.4 (1.9,8.6)33/74.0 (1.0,8.2)0.83BMI <2525/21.5 (0.2,5.4)75/184.9 (2.9,7.7)101/173.4 (2.0,5.5)0.1625-2919/54.9 (1.6,11.3)68/92.8 (1.3,5.2)36/42.1 (0.6,5.4)0.4530+23/54.8 (1.6,11.2)76/123.0 (1.6,5.3)32/74.0 (1.6,8.2)0.67SIRs compare observed numer of BCs to expected using Iowa SEER data. Analyses account for the effects of age and calendar period. P-value is test of heterogeneity in SIRs across columns. Conclusions We found no evidence of an association between MBD and subsequent BC in women with AH. Citation Format: Vierkant RA, Degnim AC, Hartmann LC, Frank RD, Radisky DC, Visscher DW, Frost MH, Winham SJ, Ghosh K, Vachon CM. No evidence of association between mammographic breast density and risk of breast cancer in women with atypical hyperplasia. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-09-05.

Abstract Background: Fibroadenoma (FA) is a relatively common benign breast tumor that can occur in women of any age, with a peak incidence during the second and third decades. The only previous study of this lesion reported that FAs are associated with a 2.2 times increased risk of developing invasive breast cancer (BC) compared to matched controls [1]. This relative risk may increase to 3.1 among patients with complex FA, and remains elevated for decades after diagnosis. However, this study did not thoroughly account for other forms of concomitant risk factors. Our investigative team sought to examine breast cancer risk among women with non-complex and complex FA, overall and stratified by other BC risk factors. Materials and Methods: The study cohort included women between ages 18 to 85 in the Mayo Benign Breast Disease (BBD) Cohort who underwent excisional breast biopsy between 1967and1991 and were found to have a FA. FA was defined histologically as a combination of epithelial and stromal proliferation. Complex FA was defined as FA associated with any of the following features: sclerosing adenosis, epithelial calcifications, papillary apocrine change, and microcysts greater than 3.0 mm. The primary endpoint was a diagnosis of BC, determined using the Mayo medical record and questionnaire information from study participants. A single breast pathologist, blinded to the initial diagnosis and clinical outcome, performed pathology review. Observed vs. expected BC risk across levels of FA was assessed via standardized incidence ratios (SIRs), using age-stratified incidence rates from the Iowa Surveillance, Epidemiology, and End Results (SEER) registry. Analyses were carried out overall and within subgroups of involution status (none, partial, complete) and overall histology (non-proliferative disease [NP], proliferative disease without atypia [PDWA] or atypical hyperplasia [AH]). Results: Of 9097 women in the Mayo BBD Cohort, FA were identified in 2139- non-complex in 1903 (20.9%) and complex in 236 (2.6%). The greatest proportion of FA occurred in the 40–69 age range. The mean ages for women with non-complex FA and complex FA were 45.7 and 50.2 years respectively. The SIR of breast cancer in the overall BBD cohort was 1.5 (95% CI [1.4–1.6]). The SIR among women with non-complex FA was 1.5 (95% CI [1.3–1.8]), and for complex FA increased to 2.41 (95% CI [1.7–3.4]). However, women with complex FA were more likely to have other concomitant high-risk histologic features such as PDWA and incomplete involution. In stratified analyses accounting for involution status and PDWA, complex FA did not demonstrate an independent increase in BC risk. Conclusion: Complex FA does not confer an increased risk for BC beyond other established histologic features. Therefore, women with complex FA should be managed based upon a risk level consistent with the major histologic category of PDWA and/or AH. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-01-08.

Abstract Background: Optimal early detection and prevention strategies for breast cancer are predicated on our ability to accurately identify women at increased risk for disease. Current breast cancer risk prediction models rely on clinical and epidemiologic features. As demonstrated with other cancers, such as those of the cervix and colon, cancer risk assessment is enhanced when the tissue at risk is examined for evidence of premalignant abnormalities. Here, we present a multivariate model for individualized breast cancer risk prediction that incorporates tissue features identified from biopsies from women with benign breast disease (BBD). Methods: We used our cohort of more than 9000 women diagnosed with BBD at the Mayo Clinic from 1967–1991, and identified a nested case:control series of 377 women who developed cancer (cases) matched with 734 women who did not (controls). We identified a set of variables that either alone or in two-way interactions contributed to a multivariable risk prediction model. We combined this relative risk model with the baseline incidence of breast cancer and the baseline hazard of death from our full BBD cohort to develop a risk prediction tool that computes absolute risk estimates for breast cancer. We calculated 5-year risk predictions for these cases and controls using our model and using the Gail model and compared c-statistics from these risk predictions. We validated our model using an independent set of 378 breast cancer cases and 728 matched controls drawn from our BBD cohort. Results: Cases and controls in the model development data set differed significantly on a number of features when examined individually. Those included in a multivariable relative risk model for breast cancer among women with BBD are shown below. After including interactions between lobular involution, and histologic impression, with age at first live birth/number of children, and degree of involution with sclerosing adenosis, we devised a model that predicts the absolute risk of breast cancer. Predicted five-year risks in the model development series, we observed a c-statistic of 0.66, higher than the c-statistic of 0.61 for the Gail model. With risk prediction estimates from our validation series of cases and matched controls, the c-statistic of our model decreased to 0.59 and the c-statistic for the Gail model was 0.55. Conclusion: We have identified an initial risk prediction model for breast cancer in women with BBD. The identified model includes basic demographic information as well as a number of histologic features of the tissue samples. Its initial performance is promising, providing improved discrimination over the Gail model in our replication data set. Further work is needed to identify features which might provide additional predictive information for breast cancer risk. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-12-03.

Abstract Background: Women with benign breast disease are at elevated breast cancer risk. In order to accurately predict a woman's individual risk of breast cancer, a breast cancer risk-prediction model is needed that incorporates significant breast cancer risk factors. This report describes two factors: tissue based assessment of lobular involution, and radiological marker- mammographic density (MD). Lobular involution, or physiologic atrophy of the breast glandular epithelium, is inversely associated with breast cancer risk. MD is a strong positive risk factor for breast cancer. With increasing age, the extent of lobular involution increases while MD decreases. However, it is unclear whether involution and MD represent independent breast cancer risk factors. We examined breast cancer risk associated with lobular involution and MD in women with benign breast disease (BBD) to determine whether these features are independently associated with breast cancer risk.Methods: Using the Mayo Clinic Surgical and Pathology Indices, 9376 women ages 18 to 85 with benign excisional breast biopsy between January 1, 1967 and December 31, 1991 were identified and formed the Mayo BBD cohort. We studied a sub-cohort of women diagnosed with BBD between 1985 and 1991 (when MD was clinically assessed and recorded) who had a mammogram within 6 months of the BBD diagnosis. Breast cancer outcomes were determined through the Mayo medical records and a study-specific questionnaire. Lobular involution extent was assessed in background tissue as 'none' (0% lobules involuted), 'partial' (1-74% lobules involuted) or 'complete' (≥75% lobules involuted). MD was classified as Wolfe's parenchymal pattern (PP) as N1/ fatty; P1; P2; and DY/ homogenously dense. Hazard ratios and confidence intervals were calculated using Cox regression analyses, adjusting for confounders: age, parity, BMI, BBD histology, menopausal status, family history, PP and involution extent.Results: A total of 2666 women in the Mayo BBD cohort, with biopsies between 1985 and 1991, had a mammogram within 6 months of the breast biopsy. The mean age at biopsy was 54.6 years. After a mean follow-up of 13.3 years, 172 (6.5%) women developed breast cancer. After adjustment for PP and other confounders, women with no or partial involution had elevated risk compared to women with complete involution (HR 2.62 [95% CI 1.39, 4.94] for no involution and 1.61 [95% CI 1.03, 2.53] for partial involution; complete involution as reference group; p for trend 0.003). Moreover, women with dense breasts were at greater risk compared to women with nondense breasts (HR 1.67 [95% CI 1.0, 2.73] for DY pattern, 1.96 [95% CI 1.2 – 3.21] for P2, 1.23 [95% CI 0.67, 2.26] for P1; N1 category as reference group; p for trend 0.02). Multivariate analyses also showed that women with the combination of no involution and dense breasts had greater risk compared to those with complete involution and nondense breasts (HR 4.08 [95% CI 1.72, 9.68]).Conclusion: Lobular involution and MD are both risk factors for breast cancer; this report is the first to demonstrate that each provides unique information about breast cancer risk. These findings emphasize the potential for inclusion of both these factors in future breast cancer risk-prediction models. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6064.

Abstract Abstract #62 Background: Breast cancer is the leading cause of cancer deaths in younger women (25 to 49 years of age). Young women with breast cancer also have worse overall survival and increased risk of recurrence compared to older women with breast cancer. Innovative approaches to understanding risk factors and tissue characteristics for the younger population can improve understanding of breast cancer etiology and enhance risk-stratification for these women. This study was aimed at examining breast cancer risk factors among young women (<50 years) with BBD. Materials and Methods: Utilizing the Mayo Clinic Surgical and Pathology Indices, women ages 18 to 85 who had benign excisional breast biopsy between January 1, 1967 and December 31, 1991 were identified. The diagnosis of breast cancer served as the study endpoint and was determined using the Mayo medical record and questionnaire information from study participants. The breast pathologist, blinded to the initial diagnosis and clinical outcome, performed pathology review. BBD was classified as non-proliferative disease (NPD), proliferative disease without atypia (PDWA), or atypical hyperplasia (AH). Age-related lobular involution (reduction in number and size of acini per lobule) was classified as none-0%, partial- 1 to74%, or complete- >75% involution. Relative risk (RR) was estimated by comparing the number of observed breast cancers with the number expected, based on breast cancer rates in the Iowa Surveillance, Epidemiology, and End Results registry. Results: Of the 9376 women in the Mayo BBD cohort, 4460 women were aged <50 years at BBD diagnosis and formed the study cohort. The mean age at BBD diagnosis was 39.4 (+ 8.3) years. With a median follow-up of 20 years, 326 breast cancer cases were identified. The histologic findings were NPD in 72% of women, PDWA in 26%, and AH in 2%. The relative risk of breast cancer for the overall cohort of young women with BBD was 1.5 (95% CI [1.4, 1.7]). The relative risk among those with AH was 6.9 (95% CI [4.6, 10.1), compared with a RR of 2.0 (95% CI [1.7, 2.4]) for PDWA, and RR of 1.2 (95% CI [1.0, 1.4]) for NPD. Risk was associated with extent of lobular involution (RR for no involution was 1.7 (95%CI [1.4, 2.1]); partial involution 1.4 (95%CI [1.2, 1.7]); complete involution 0.7 (95%CI [0.3, 1.4]). Family history was available for 83% of the cohort and RR was 2.2 (95% CI [1.7, 2.8]) for women with strong family history and was 1.3 (95% CI [1.1, 1.6]) for women with no family history. Discussion: Young women with BBD are at increased risk of breast cancer. Risk is high in women with atypical hyperplasia, and those with a family history of breast cancer. Lobular involution is associated with reduced breast cancer risk in this population, suggesting a role in modifying breast cancer risk. These findings suggest the need for further research in this population, along with tissue-based studies to examine the processes leading to breast cancer, and enable identification of those women at highest risk. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 62.

Abstract Abstract #4037 Background: Mammographic breast density is a strong and consistent risk factor for breast cancer. Women with dense tissue in over 60 to 75% of the breast are at 4 to 6 times greater risk than women with little or no density. However, the biology of breast density is not well understood and studies at the tissue level are limited. We present the first report of a tissue-based study of breast density, sampling mammographically dense and non-dense areas of the breast of healthy women with the goal of examining histologic correlates.
 Materials and Methods: Healthy women volunteers aged 40 to 85 years, with no breast symptoms, normal screening mammogram within 6 months, and no personal history of breast cancer were considered eligible. Women with breast-related symptoms, those on endocrine therapy, or with bleeding tendencies were excluded from participation. Sixty consecutive eligible women were enrolled in the study- results are based on the first 34 participants. Eligible women underwent an ultrasound-guided, core-needle breast biopsy of mammographically dense and non-dense areas of the breast, performed by a single experienced radiologist. Quantitative assessment of breast tissue from dense and non-dense areas was performed for epithelium, stroma, and fat. In addition, we assessed the difference in the extent of lobular involution (complete, partial and none) between dense and non-dense areas. We used means and SD to describe distributions in each tissue type. Signed rank test was used to assess within woman differences between dense and non-dense tissue.
 Results: The mean age of the participants was 50.1 years (range 40 to 79 years). The histological findings are outlined below.
 
 Dense tissue is comprised of increased stroma and epithelium and decreased fat, consistent with prior reports on breast density. The finding of 'no involution' was greater in dense tissue compared to non-dense tissue (24% versus 8.8%); non-dense tissue had greater proportion of complete involution compared to dense tissue (82.5% versus 35.2%).
 Discussion: This report is the first to quantify histology in tissue sampled from dense and non-dense regions of the healthy breast. We find a dramatic difference in tissue composition between dense and non-dense tissue in the breast. Future studies using this tissue to assess molecular markers will further help to characterize pathways through which density may increase breast cancer risk. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4037.

Abstract Abstract #4033 Background: Aromatase activity within the breast is a source of estrogen that may cause breast cancer. Mammographic density (MD) is a risk factor for breast cancer whose biologic basis is unknown. Our study compared aromatase expression in tissue from dense and non-dense areas of the breasts of healthy volunteers.
 Methods: Participants were 40+ yrs, had a screening mammogram with visible MD, no history of cancer and were not on endocrine therapy. Ultrasound-guided core biopsies were done within 6 months of mammography to obtain three paired cores from mammographically dense and non-dense regions of the breast. Immunostaining for aromatase expression employed the streptavidin-biotin amplification method using the recently developed 677 mouse monoclonal antibody. Immunoreactivity (IR) was scored in terms of proportion of cells staining positive for aromatase (PPC) (0=<1%, 1=1-25%, 2=26-50%, 3=51+% (and 4=75%+ for adipocytes)) and relative immunointensity (0=none, 1=weak, 2=moderate, 3=intense) for each cell type (stroma, normal ductal epithelium, adipocytes). A composite score weighting the PPC by their relative intensity (range 0-9; 0-12 for adipocytes) was also calculated. The sum of the composite score across the three cell types provided a global assessment of aromatase IR. Repeated measures analyses evaluated differences in aromatase IR for dense compared to non-dense tissue within and across cell types. Parameter estimates (β) indicated the average difference between dense and non-dense IR.
 Results: 18 (37%) of the 49 participants were premenopausal (median age 46 yrs). Summing across cell types, the global composite score showed increased aromatase IR on sections sampled from dense vs. non-dense regions (β=5.3,p<0.001). This global difference reflected increased aromatase IR in the stroma and normal ductal epithelium from dense sections (vs. non-dense). For 42 women with >1% stromal cells on each section, there was evidence for increased IR on dense sections as indicated by the greater PPCs (β=0.9), relative intensity (β=0.7) and composite score (β=2.7)(p's<0.001). Similarly, for 20 women with >1% normal ductal epithelium in both dense and non-dense sections, there was a greater composite score (β=1.4,p=0.004) for cells on dense sections although differences for PPC (β=0.3,p=0.11) and relative intensity (β=0.3,p=0.09) did not reach statistical significance. No differences were seen in IR for adipocytes from the two density regions (46 women). Findings were unchanged with adjustment for covariates, including proportions of each cell type per section.
 Conclusions: There is strong evidence for increased aromatase expression in the stromal and normal ductal epithelium of dense vs. non-dense tissue. These results support ongoing research into mammographic density as a biomarker of effect of aromatase inhibitors. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4033.