Publications by authors named "Laura C Collins"

115 Publications

Mucin Neovascularization as a Diagnostic Aid to Distinguish Mucinous Carcinomas From Mucocele-like Lesions in Breast Core Needle Biopsies.

Am J Surg Pathol 2021 Sep 21. Epub 2021 Sep 21.

Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School Department of Pathology, Brigham and Women's Hospital and Harvard Medical School Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA.

The distinction between mucinous carcinomas (MCs) and mucocele-like lesions (MLLs), particularly those containing detached epithelial fragments, can be problematic in the limited samples afforded by breast core needle biopsies (CNBs). Neovascularization of mucin has been proposed as a criterion to distinguish MC from MLL, but its value in helping to categorize mucin-producing breast lesions in CNB has not been previously investigated. To address this, we evaluated mucin neovascularization on hematoxylin and eosin (H&E)-stained sections of 140 CNB containing mucin-producing breast lesions including 52 MC, 17 mucin-producing ductal carcinoma in situ (mDCIS), and 71 MLL. In 116 cases with sufficient remaining material (42 MC, 16 mDCIS, and 58 MLL), we also assessed mucin neovascularization on CD31 immunostains. On H&E-stained sections, neovascularization of mucin, defined as delicate, thin-walled microvessels in mucin, and unassociated with fibrous septae, was identified significantly more frequently in MC than in MLL (69.2% vs. 14.1%; P=0.0001). The difference in the frequency of mucin neovascularization between MC and MLL was even greater on CD31 immunostains (97.6% vs. 13.8%, P<0.00001). The sensitivity, specificity, positive predictive value, and negative predictive value of mucin neovascularization for categorizing a lesion as MC were 69.2%, 85.8%, 78.3%, and 79.2%, respectively, for H&E-stained sections and 97.6%, 86.2%, 83.7%, and 98.0%, respectively, for CD31 immunostains. We conclude that mucin neovascularization is significantly more common in MC than in MLL in breast CNB on H&E-stained sections and particularly on CD31 immunostains and may be a valuable adjunct in distinguishing between MC and MLL in problematic cases.
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http://dx.doi.org/10.1097/PAS.0000000000001814DOI Listing
September 2021

Reliability of a computational platform as a surrogate for manually interpreted immunohistochemical markers in breast tumor tissue microarrays.

Cancer Epidemiol 2021 Oct 2;74:101999. Epub 2021 Aug 2.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.

Background: Pathologist and computational assessments have been used to evaluate immunohistochemistry (IHC) in epidemiologic studies. We compared Definiens Tissue Studio® to pathologist scores for 17 markers measured in breast tumor tissue microarrays (TMAs) [AR, CD20, CD4, CD8, CD163, EPRS, ER, FASN, H3K27, IGF1R, IR, Ki67, phospho-mTOR, PR, PTEN, RXR, and VDR].

Methods: 5 914 Nurses' Health Study participants, diagnosed 1976-2006 (NHS) and 1989-2006 (NHS-II), were included. IHC was conducted by the Dana-Farber/Harvard Cancer Center Specialized Histopathology Laboratory. The percent of cells staining positive was assessed by breast pathologists. Definiens output was used to calculate a weighted average of percent of cells staining positive across TMA cores for each marker. Correlations between pathologist and computational scores were evaluated with Spearman correlation coefficients. Receiver-operator characteristic curves were constructed, using pathologist scores as comparison.

Results: Spearman correlations between pathologist and Definiens assessments ranged from weak (RXR, rho=-0.05; CD163, rho = 0.10) to strong (Ki67, rho = 0.79; pmTOR, rho = 0.77). The area under the curve was >0.70 for all markers except RXR.

Conclusion: Our data indicate that computational assessments exhibit variable correlations with interpretations made by an expert pathologist, depending on the marker evaluated. This study provides evidence supporting the use of computational platforms for IHC evaluation in large-scale epidemiologic studies, with the caveat that pilot studies are necessary to investigate agreement with expert assessments. In sum, computational platforms may provide greater efficiency and facilitate high-throughput epidemiologic analyses.
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http://dx.doi.org/10.1016/j.canep.2021.101999DOI Listing
October 2021

Healthful and Unhealthful Plant-Based Diets and Risk of Breast Cancer in U.S. Women: Results from the Nurses' Health Studies.

Cancer Epidemiol Biomarkers Prev 2021 Jul 21. Epub 2021 Jul 21.

Channing Division of Network Medicine, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Background: Plant-based diets have been associated with lower risk of various diseases, including type 2 diabetes, cardiovascular disease, and other cardiometabolic risk factors. However, the association between plant-based diet quality and breast cancer remains unclear.

Methods: We prospectively followed 76,690 women from the Nurses' Health Study (NHS, 1984-2016) and 93,295 women from the NHSII (1991-2017). Adherence to an overall plant-based diet index (PDI), a healthful PDI (hPDI), and an unhealthful PDI (uPDI) was assessed using previously developed indices. Cox proportional hazards models were used to estimate HR and 95% confidence intervals (CI) for incident invasive breast cancer.

Results: Over 4,841,083 person-years of follow-up, we documented 12,482 incident invasive breast cancer cases. Women with greater adherence to PDI and hPDI were at modestly lower risk of breast cancer [(HR, 0.89; 95% CI, 0.84-0.95); (HR, 0.89; 95% CI, 0.83-0.94)]. We observed significant heterogeneity by estrogen receptor (ER) status, with the strongest inverse association between hPDI and breast cancer observed with ER-negative tumors [HR, 0.77; 95% CI, 0.65-0.90; < 0.01]. We also found an inverse association between extreme quintiles of healthy plant foods and ER-negative breast cancer [HR, 0.74; 95% CI, 0.61-0.88; < 0.01].

Conclusions: This study provides evidence that adherence to a healthful plant-based diet may reduce the risk of breast cancer, especially those that are more likely to be aggressive tumors.

Impact: This is the first prospective study investigating the relation between healthful and unhealthful plant-based dietary indices and risk of total and subtype-specific breast cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0352DOI Listing
July 2021

Associations of reproductive breast cancer risk factors with breast tissue composition.

Breast Cancer Res 2021 07 5;23(1):70. Epub 2021 Jul 5.

Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA.

Background: We investigated the associations of reproductive factors with the percentage of epithelium, stroma, and fat tissue in benign breast biopsy samples.

Methods: This study included 983 cancer-free women with biopsy-confirmed benign breast disease (BBD) within the Nurses' Health Study and Nurses' Health Study II cohorts. The percentage of each tissue type (epithelium, stroma, and fat) was measured on whole-section images with a deep-learning technique. All tissue measures were log-transformed in all the analyses to improve normality. The data on reproductive variables and other breast cancer risk factors were obtained from biennial questionnaires. Generalized linear regression was used to examine the associations of reproductive factors with the percentage of tissue types, while adjusting for known breast cancer risk factors.

Results: As compared to parous women, nulliparous women had a smaller percentage of epithelium (β = - 0.26, 95% confidence interval [CI] - 0.41, - 0.11) and fat (β = - 0.34, 95% CI - 0.54, - 0.13) and a greater percentage of stroma (β = 0.04, 95% CI 0.01, 0.08). Among parous women, the number of children was inversely associated with the percentage of stroma (β per child = - 0.01, 95% CI - 0.02, - 0.00). The duration of breastfeeding of ≥ 24 months was associated with a reduced proportion of fat (β = - 0.30, 95% CI - 0.54, - 0.06; p-trend = 0.04). In a separate analysis restricted to premenopausal women, older age at first birth was associated with a greater proportion of epithelium and a smaller proportion of stroma.

Conclusions: Our findings suggest that being nulliparous as well as having a fewer number of children (both positively associated with breast cancer risk) is associated with a smaller proportion of epithelium and a greater proportion of stroma, potentially suggesting the importance of epithelial-stromal interactions. Future studies are warranted to confirm our findings and to elucidate the underlying biological mechanisms.
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http://dx.doi.org/10.1186/s13058-021-01447-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258947PMC
July 2021

Sugar-Sweetened Beverages, Artificially Sweetened Beverages, and Breast Cancer Risk: Results From 2 Prospective US Cohorts.

J Nutr 2021 Sep;151(9):2768-2779

Channing Division of Network Medicine, Department of Medicine, Brigham & Women's Hospital, and Harvard Medical School, Boston, MA, USA.

Background: Whether consumption of sugar-sweetened beverages (SSBs) or artificially sweetened beverages (ASBs) is associated with the risk of breast cancer is of public health interest.

Objectives: We sought to evaluate associations between consumption of SSBs and ASBs and risks of total and subtype-specific breast cancer.

Methods: We followed 82,713 women from the Nurses' Health Study (1980 to 2016) and 93,085 women from the Nurses' Health Study II (1991 to 2017). Cumulatively averaged intakes of SSBs and ASBs from FFQs were tested for associations with incident breast cancer cases and subtypes using Cox regression models. We also evaluated the associations stratified by menopausal status, physical activity, BMI, and alcohol intake.

Results: We documented 11,379 breast cancer cases during 4,655,153 person-years of follow-up. Consumption of SSBs or ASBs was not associated with total breast cancer risk: pooled HRs comparing extreme categories (≥1/day compared with <1/month) were 1.03 (95% CI, 0.95-1.12) and 0.96 (95% CI, 0.91-1.02), respectively. We observed a suggestive interaction by BMI using pooled data (P-interaction = 0.08), where a modestly higher risk of breast cancer with each serving per day increment of SSBs was found in lean women (HR, 1.06; 95% CI, 1.01-1.11) but not among overweight or obese women (HR, 1.00; 95% CI, 0.95-1.06). Moreover, in the pooled, fully adjusted analysis, compared to infrequent consumers (<1/month), those who consumed ≥1 serving of ASBs per day had a lower risk of luminal A breast tumors (HR, 0.90; 95% CI, 0.80-1.01; P-trend = 0.02).

Conclusions: Although no significant associations were observed overall, consumption of SSBs was associated with a slightly higher risk of breast cancer among lean women. This finding could have occurred by chance and needs confirmation. Our findings also suggest no substantial increase in the risk of breast cancer with consumption of ASBs.
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http://dx.doi.org/10.1093/jn/nxab172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417930PMC
September 2021

TDLU Involution and Breast Cancer Risk-Reply.

Cancer Epidemiol Biomarkers Prev 2021 04;30(4):798

Department of Population Health Sciences, Weill Cornell Medicine, New York, New York.

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http://dx.doi.org/10.1158/1055-9965.EPI-20-1748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8030734PMC
April 2021

The impact of mammographic screening on the subsequent breast cancer risk associated with biopsy-proven benign breast disease.

NPJ Breast Cancer 2021 Mar 5;7(1):23. Epub 2021 Mar 5.

Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Data on the risk of breast cancer following a benign breast disease (BBD) diagnosis were derived predominantly from populations of women biopsied before the widespread use of mammographic screening and in whom these lesions were mostly incidental findings. Whether or not similar risk associations are seen when these lesions are detected in mammographically screened populations is unknown. To address this, we examined the variation in BBD and breast cancer risk associations by the calendar time of BBD diagnosis (pre- vs. post-mammography era [before vs. 1985 and after]) in a nested case-control study within the Nurses' Health Study (NHS) and NHSII BBD subcohort (488 cases; 1908 controls). We performed logistic regression analysis, adjusting for matching factors and potential confounders, to estimate odds ratio (ORs) and 95% confidence interval (CI) for the association between BBD subtype (non-proliferative, proliferative without atypia, proliferative with atypical hyperplasia (AH)) and subsequent breast cancer risk. When compared with non-proliferative lesions, both proliferative lesions without atypia (PWA) and AHs were associated with similar levels of risk in the pre-mammographic (pre) and post-mammographic (post) time periods (PWA: OR [95% CI] = 1.73 [1.27, 2.36] pre vs. 1.12 [0.73, 1.74] post; AH: 4.41 [2.90, 6.70] pre vs. 3.69 [2.21, 6.15] post). The interaction by mammography era was not statistically significant (p-interaction = 0.47). These results suggest that the risk associations reported for BBD subtypes in the pre-mammography era remain valid for BBD detected after the widespread implementation of mammographic screening.
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http://dx.doi.org/10.1038/s41523-021-00225-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935945PMC
March 2021

Deep Learning Image Analysis of Benign Breast Disease to Identify Subsequent Risk of Breast Cancer.

JNCI Cancer Spectr 2021 Feb 11;5(1):pkaa119. Epub 2021 Jan 11.

Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Background: New biomarkers of risk may improve breast cancer (BC) risk prediction. We developed a computational pathology method to segment benign breast disease (BBD) whole slide images into epithelium, fibrous stroma, and fat. We applied our method to the BBD BC nested case-control study within the Nurses' Health Studies to assess whether computer-derived tissue composition or a morphometric signature was associated with subsequent risk of BC.

Methods: Tissue segmentation and nuclei detection deep-learning networks were established and applied to 3795 whole slide images from 293 cases who developed BC and 1132 controls who did not. Percentages of each tissue region were calculated, and 615 morphometric features were extracted. Elastic net regression was used to create a BC morphometric signature. Associations between BC risk factors and age-adjusted tissue composition among controls were assessed using analysis of covariance. Unconditional logistic regression, adjusting for the matching factors, BBD histological subtypes, parity, menopausal status, and body mass index evaluated the relationship between tissue composition and BC risk. All statistical tests were 2-sided.

Results: Among controls, direction of associations between BBD subtypes, parity, and number of births with breast composition varied by tissue region; select regions were associated with childhood body size, body mass index, age of menarche, and menopausal status (all <.05). A higher proportion of epithelial tissue was associated with increased BC risk (odds ratio = 1.39, 95% confidence interval = 0.91 to 2.14, for highest vs lowest quartiles, =.047). No morphometric signature was associated with BC.

Conclusions: The amount of epithelial tissue may be incorporated into risk assessment models to improve BC risk prediction.
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http://dx.doi.org/10.1093/jncics/pkaa119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898083PMC
February 2021

Variability in grading of ductal carcinoma in situ among an international group of pathologists.

J Pathol Clin Res 2021 May 23;7(3):233-242. Epub 2021 Feb 23.

Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

The prognostic value of cytonuclear grade in ductal carcinoma in situ (DCIS) is debated, partly due to high interobserver variability and the use of multiple guidelines. The aim of this study was to evaluate interobserver agreement in grading DCIS between Dutch, British, and American pathologists. Haematoxylin and eosin-stained slides of 425 women with primary DCIS were independently reviewed by nine breast pathologists based in the Netherlands, the UK, and the USA. Chance-corrected kappa (κ ) for association between pathologists was calculated based on a generalised linear mixed model using the ordinal package in R. Overall κ for grade of DCIS (low, intermediate, or high) was estimated to be 0.50 (95% confidence interval [CI] 0.44-0.56), indicating a moderate association between pathologists. When the model was adjusted for national guidelines, the association for grade did not change (κ = 0.53; 95% CI 0.48-0.57); subgroup analysis for pathologists using the UK pathology guidelines only had significantly higher association (κ = 0.58; 95% CI 0.56-0.61). To assess if concordance of grading relates to the expression of the oestrogen receptor (ER) and HER2, archived immunohistochemistry was analysed on a subgroup (n = 106). This showed that non-high grade according to the majority opinion was associated with ER positivity and HER2 negativity (100 and 89% of non-high grade cases, respectively). In conclusion, DCIS grade showed only moderate association using whole slide images scored by nine breast pathologists. As therapeutic decisions and inclusion in ongoing clinical trials are guided by DCIS grade, there is a pressing need to reduce interobserver variability in grading. ER and HER2 might be supportive to prevent the accidental and unwanted inclusion of high-grade DCIS in such trials.
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http://dx.doi.org/10.1002/cjp2.201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073001PMC
May 2021

Surgical Treatment after Neoadjuvant Systemic Therapy in Young Women with Breast Cancer: Results from a Prospective Cohort Study.

Ann Surg 2020 Dec 23;Publish Ahead of Print. Epub 2020 Dec 23.

Department of Surgery, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, South Korea Dana-Farber Cancer Institute, Boston, MA, USA Brigham and Women's Hospital, Boston, MA, USA Mayo Clinic, Rochester, MN, USA Stanford University, Palo Alto, CA, USA Beth Israel Deaconess Medical Center, Boston, MA, USA Massachusetts General Hospital, Boston, MA, USA University of Colorado Cancer Center, Aurora, CO, USA Sunnybrook Health Sciences Centre, Toronto, Ontario, USA Metrowest Medical Center, Framingham, MA, USA.

Objective: We aimed to investigate eligibility for breast-conserving surgery (BCS) pre- and post-neoadjuvant systemic therapy (NST), and trends in the surgical treatment of young breast cancer patients.

Background: Young women with breast cancer are more likely to present with larger tumors and aggressive phenotypes, and may benefit from NST. Little is known about how response to NAC influences surgical decisions in young women.

Methods: The Young Women's Breast Cancer Study (YWS), a multicenter prospective cohort of women diagnosed with breast cancer at age ≤40, enrolled 1302 patients from 2006 to 2016. Disease characteristics, surgical recommendations, and reasons for choosing mastectomy among BCS-eligible patients were obtained through the medical record. Trends in use of NST, rate of clinical and pathologic complete response (cCR and pCR), and surgery were also assessed.

Results: Of 1117 women with unilateral stage I-III breast cancer, 315 (28%) received NST. Pre-NST, 26% were BCS eligible, 17% were borderline eligible, and 55% were ineligible. After NST, BCS eligibility increased from 26% to 42% (p < 0.0001). Among BCS-eligible patients after NST (n = 133), 41% chose mastectomy with reasons being patient preference (53%), BRCA or TP53 mutation (35%) and family history (5%). From 2006 to 2016, the rates of NST (p = 0.0012), cCR (p < 0.0001) and bilateral mastectomy (p < 0.0001) increased, but the rate of BCS did not increase (p = 0.34).

Conclusion: While the proportion of young women eligible for BCS increased after NST, many patients choose mastectomy, suggesting that surgical decisions are often driven by factors beyond extent of disease and treatment response.
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http://dx.doi.org/10.1097/SLA.0000000000004296DOI Listing
December 2020

Early-Life and Adult Adiposity, Adult Height, and Benign Breast Tissue Composition.

Cancer Epidemiol Biomarkers Prev 2021 04 7;30(4):608-615. Epub 2020 Dec 7.

Department of Population Health Sciences, Weill Cornell Medicine, New York, New York.

Background: Early-life and adult anthropometrics are associated with breast density and breast cancer risk. However, little is known about whether these factors also influence breast tissue composition beyond what is captured by breast density among women with benign breast disease (BBD).

Methods: This analysis included 788 controls from a nested case-control study of breast cancer within the Nurses' Health Study BBD subcohorts. Body fatness at ages 5 and 10 years was recalled using a 9-level pictogram. Weight at age 18, current weight, and height were reported via questionnaires. A deep-learning image analysis was used to quantify the percentages of epithelial, fibrous stromal, and adipose tissue areas within BBD slides. We performed linear mixed models to estimate beta coefficients (β) and 95% confidence intervals (CI) for the relationships between anthropometrics and the log-transformed percentages of individual tissue type, adjusting for confounders.

Results: Childhood body fatness (level ≥ 4.5 vs. 1), BMI at age 18 (≥23 vs. <19 kg/m), and current adult BMI (≥30 vs. <21 kg/m) were associated with higher proportions of adipose tissue [β (95% CI) = 0.34 (0.03, 0.65), 0.19 (-0.04-0.42), 0.40 (0.12, 0.68), respectively] and lower proportions of fibrous stromal tissue [-0.05 (-0.10, 0.002), -0.03 (-0.07, 0.003), -0.12 (-0.16, -0.07), respectively] during adulthood (all < 0.04). BMI at age 18 was also inversely associated with epithelial tissue ( = 0.03). Adult height was not associated with any of the individual tissue types.

Conclusions: Our data suggest that body fatness has long-term impacts on breast tissue composition.

Impact: This study contributes to our understanding of the link between body fatness and breast cancer risk..
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026662PMC
April 2021

Tumor phenotype and concordance in synchronous bilateral breast cancer in young women.

Breast Cancer Res Treat 2021 Apr 26;186(3):815-821. Epub 2020 Nov 26.

Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA.

Purpose: Synchronous bilateral breast cancer is uncommon, and its pattern and incidence among younger women is unknown. Here we report the incidence, phenotypes, and long-term oncologic outcomes of bilateral breast cancer in women enrolled in the Young Women's Breast Cancer Study (YWS).

Methods: The YWS is a multi-center, prospective cohort study of women with breast cancer diagnosed at age ≤ 40 years. Those with synchronous bilateral breast cancer formed our study cohort. Tumor phenotypes were categorized as luminal A (hormone receptor (HR)+/HER2-/grade 1/2), luminal B (HR+ /HER2+ or HER2- and grade 3), HER2-enriched (HR-/HER2+), or basal-like (HR-/HER2-). Descriptive statistics were used to evaluate tumor phenotypes of bilateral cancers for concordance.

Results: Among 1302 patients enrolled in the YWS, 21 (1.6%) patients had synchronous bilateral disease. The median age of diagnosis was 38 years (range 18-40 years). Seventeen (81.0%) underwent genetic testing with 6 found to have pathogenic germline mutations in BRCA1, BRCA2, or TP53. The majority of patients (76.2%) underwent bilateral mastectomy. On pathology, 2 patients had bilateral in-situ disease, 6 had unilateral invasive and contralateral in-situ disease, and 13 had bilateral invasive disease. Of those with bilateral invasive disease, 10 (76.9%) had bilateral luminal tumors and, when fully characterized, 6 were of the same luminal subtype. Only 1 patient had bilateral basal-like breast cancer. At median follow-up of 8.2 years, 14 patients are alive with no recurrent disease.

Conclusions: Bilateral breast cancer is uncommon among young women diagnosed with breast cancer at age ≤ 40. In our cohort, the majority of invasive tumors were of the luminal phenotype, though some differed by grade or HER2 status. These findings support the need for thorough pathologic workup of bilateral disease when it is found in young women with breast cancer to determine risk and tailor treatment.
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http://dx.doi.org/10.1007/s10549-020-06027-0DOI Listing
April 2021

Testosterone therapy and breast histopathological features in transgender individuals.

Mod Pathol 2021 01 16;34(1):85-94. Epub 2020 Sep 16.

Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Testosterone therapy (TT) is administered to enhance masculinization in transgender individuals. The long-term effect of exogenous testosterone on breast tissues remains unclear. Our study evaluated the modulation of breast morphology by TT in transgender individuals with special attention to duration of TT. We reviewed 447 breast surgical specimens from gender affirming chest-contouring surgery, and compared histopathological findings including degree of lobular atrophy, and atypical and non-atypical proliferations between subjects who did (n = 367) and did not (n = 79) receive TT. TT for one patient was unknown. TT for >12 months was associated with seven histopathological features. Longer duration of TT was significantly associated with higher degrees of lobular atrophy (p < 0.001). This relationship remained significant after accounting for age at surgery, ethnicity, body mass index, and presurgical oophorectomy (adjusted p < 0.001). Four types of lesions were more likely to be absent in breast tissues exposed to longer durations of TT: cysts (median = 16.2 months; p < 0.01; adjusted p = 0.01), fibroadenoma (median = 14.8 months; p = 0.02; adjusted p = 0.07), pseudoangiomatous stromal hyperplasia (median = 17.0 months; p < 0.001; adjusted p < 0.001), and papillomas (median = 14.7 months; p = 0.04; adjusted p = 0.20). Columnar cell change and mild inflammation were also less likely to occur in subjects receiving TT (p < 0.05), but were not linked to the duration of TT. Atypia and ductal carcinoma in situ were detected in 11 subjects (2.5%) all of whom received TT ranging from 10.1 to 64.1 months. The incidental findings of high-risk lesions and carcinoma as well as the risk of cancer in residual breast tissue after chest-contouring surgery warrant the consideration of culturally sensitive routine breast cancer screening protocols for transgender men and masculine-centered gender nonconforming individuals. Long-term follow-up studies and molecular investigations are needed to understand the breast cancer risk of transgender individuals who receive TT.
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http://dx.doi.org/10.1038/s41379-020-00675-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854981PMC
January 2021

Automated Quantitative Measures of Terminal Duct Lobular Unit Involution and Breast Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 11 11;29(11):2358-2368. Epub 2020 Sep 11.

Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Background: Manual qualitative and quantitative measures of terminal duct lobular unit (TDLU) involution were previously reported to be inversely associated with breast cancer risk. We developed and applied a deep learning method to yield quantitative measures of TDLU involution in normal breast tissue. We assessed the associations of these automated measures with breast cancer risk factors and risk.

Methods: We obtained eight quantitative measures from whole slide images from a benign breast disease (BBD) nested case-control study within the Nurses' Health Studies (287 breast cancer cases and 1,083 controls). Qualitative assessments of TDLU involution were available for 177 cases and 857 controls. The associations between risk factors and quantitative measures among controls were assessed using analysis of covariance adjusting for age. The relationship between each measure and risk was evaluated using unconditional logistic regression, adjusting for the matching factors, BBD subtypes, parity, and menopausal status. Qualitative measures and breast cancer risk were evaluated accounting for matching factors and BBD subtypes.

Results: Menopausal status and parity were significantly associated with all eight measures; select TDLU measures were associated with BBD histologic subtype, body mass index, and birth index ( < 0.05). No measure was correlated with body size at ages 5-10 years, age at menarche, age at first birth, or breastfeeding history ( > 0.05). Neither quantitative nor qualitative measures were associated with breast cancer risk.

Conclusions: Among Nurses' Health Studies women diagnosed with BBD, TDLU involution is not a biomarker of subsequent breast cancer.

Impact: TDLU involution may not impact breast cancer risk as previously thought.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642012PMC
November 2020

Precision pathology as applied to breast core needle biopsy evaluation: implications for management.

Authors:
Laura C Collins

Mod Pathol 2021 01 2;34(Suppl 1):48-61. Epub 2020 Sep 2.

Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA.

With the shift to de-escalation of therapy for some breast cancers and fewer surgical excisions for high-risk lesions identified on breast imaging studies at one end of the spectrum, and the greater use of neoadjuvant systemic therapy at the other end, pathologists are ever more critical in guiding management decisions for women with breast disease following core needle biopsy. One important consequence of this shift in management paradigms is the elimination of the opportunity for a "second-look" with the excision specimen to confirm or refine the diagnosis rendered on core needle biopsy. Thus, not only is there the imperative for accuracy and precision of core needle biopsy diagnoses, increasingly it is the only opportunity for that diagnosis.
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http://dx.doi.org/10.1038/s41379-020-00666-wDOI Listing
January 2021

Erythrocyte membrane fatty acids and breast cancer risk by tumor tissue expression of immuno-inflammatory markers and fatty acid synthase: a nested case-control study.

Breast Cancer Res 2020 07 22;22(1):78. Epub 2020 Jul 22.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.

Background: Previous studies of fatty acids and breast cancer risk have shown mixed results, which may be due in part to tumor heterogeneity. Prior research has also illustrated an important role of specific fatty acids in immune regulation, T cell function, and inflammation, indicating that the effects of specific fatty acids on breast cancer risk may vary by tumor expression of immuno-inflammatory markers. We therefore aimed to evaluate the relationships between prediagnostic erythrocyte membrane fatty acids and breast cancer risk by tumor tissue expression of immuno-inflammatory markers (CD4, CD8, CD20, CD163, COX-2) and fatty acid synthase (FAS).

Methods: We conducted a matched case-control study nested within the Nurses' Health Study II (n = 235 cases and 235 controls). Blood samples were collected from 1996 to 1999. Tumor tissue blocks were collected for cases diagnosed after blood collection and through 2006. Unconditional nominal polytomous logistic regression adjusted for matching factors and potential confounders was used to assess whether associations between fatty acids and breast cancer risk varied by tumor expression subtype, ascertained via immunohistochemistry. Odds ratios (OR) and 95% confidence intervals (CI) were estimated separately by tumor expression subtype using unconditional logistic regression.

Results: Associations between fatty acids and breast cancer risk did not vary substantially by tumor CD4, CD20, CD163, or COX-2. However, n-3 polyunsaturated fatty acids (PUFAs) were inversely associated with CD8 but not CD8 cancers (CD8 OR = 0.45, 95% CI 0.23-0.87, P = 0.02; CD8 OR = 1.19, 95% CI 0.62-2.26, P = 0.62; P = 0.04). n-6 PUFAs were suggestively inversely associated with CD8 but not CD8 cancers (CD8 OR = 0.61, 95% CI 0.32-1.14, P = 0.11; CD8 OR = 1.63, 95% CI 0.87-3.04, P = 0.12; P = 0.02). Trans fatty acids were positively associated with FAS but not FAS tumors (FAS OR = 2.94, 95% CI 1.46-5.91, P = 0.002; FAS OR = 0.99, 95% CI 0.52-1.92, P = 0.97; P = 0.01).

Conclusion: Results indicate that the effects of n-3 PUFAs, n-6 PUFAs, and trans fatty acids on breast cancer risk may vary by tumor tissue expression subtypes. Findings suggest potential immuno-modulatory and FAS-mediated mechanisms.
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http://dx.doi.org/10.1186/s13058-020-01316-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374956PMC
July 2020

Retinoblastoma protein expression and its predictors in triple-negative breast cancer.

NPJ Breast Cancer 2020 5;6:19. Epub 2020 Jun 5.

Division of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA USA.

Retinoblastoma protein (Rb) is a product of the tumor suppressor gene. Its expression is highly prevalent in luminal breast cancers and is critical to the success of cyclin-dependent kinase (CDK) 4/6 inhibitor therapy. Expression of Rb in triple-negative breast cancer (TNBC), tumors generally associated with basal biology, is not well known. However, heterogeneity among TNBC and presence of subtypes with luminal features are well described. The purpose of this study was to determine prevalence and predictors of Rb protein expression in 1-associated and sporadic TNBCs. We studied 180 TNBC patients (70 1-associated and 110 sporadic). The clinical and pathologic features of these cases were previously assessed and reported. For this study, immunohistochemical stains for Rb were performed on tissue microarray sections. Details of treatment and outcome were abstracted from medical records. Fifty-one percent of TNBC were Rb positive (≥10% nuclei staining), and 85% of these cases had ≥50% nuclei staining. Rb expression was significantly associated with sporadic TNBC (71.4% vs 49.4%;  < 0.001), androgen receptor (AR) expression (16.5% vs 3.4%;  = 0.007), histologic grade 1 or 2 (9.9% vs 2.2%;  = 0.04), and first recurrence in bone (8.8% vs 1.1%;  = 0.03). Expression of p53 was not associated with Rb expression. Expression of Rb in TNBC was significantly associated with sporadic TNBC, AR expression, lower histologic grade, and metastasis to bone. These observations characterize a TNBC subtype with features suggestive of luminal-like biology and the potential to benefit from CDK 4/6 inhibition.
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http://dx.doi.org/10.1038/s41523-020-0160-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275038PMC
June 2020

Deep learning assessment of breast terminal duct lobular unit involution: Towards automated prediction of breast cancer risk.

PLoS One 2020 15;15(4):e0231653. Epub 2020 Apr 15.

Medical Image Analysis Group, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.

Terminal duct lobular unit (TDLU) involution is the regression of milk-producing structures in the breast. Women with less TDLU involution are more likely to develop breast cancer. A major bottleneck in studying TDLU involution in large cohort studies is the need for labor-intensive manual assessment of TDLUs. We developed a computational pathology solution to automatically capture TDLU involution measures. Whole slide images (WSIs) of benign breast biopsies were obtained from the Nurses' Health Study. A set of 92 WSIs was annotated for acini, TDLUs and adipose tissue to train deep convolutional neural network (CNN) models for detection of acini, and segmentation of TDLUs and adipose tissue. These networks were integrated into a single computational method to capture TDLU involution measures including number of TDLUs per tissue area, median TDLU span and median number of acini per TDLU. We validated our method on 40 additional WSIs by comparing with manually acquired measures. Our CNN models detected acini with an F1 score of 0.73±0.07, and segmented TDLUs and adipose tissue with Dice scores of 0.84±0.13 and 0.87±0.04, respectively. The inter-observer ICC scores for manual assessments on 40 WSIs of number of TDLUs per tissue area, median TDLU span, and median acini count per TDLU were 0.71, 0.81 and 0.73, respectively. Intra-observer reliability was evaluated on 10/40 WSIs with ICC scores of >0.8. Inter-observer ICC scores between automated results and the mean of the two observers were: 0.80 for number of TDLUs per tissue area, 0.57 for median TDLU span, and 0.80 for median acini count per TDLU. TDLU involution measures evaluated by manual and automated assessment were inversely associated with age and menopausal status. We developed a computational pathology method to measure TDLU involution. This technology eliminates the labor-intensiveness and subjectivity of manual TDLU assessment, and can be applied to future breast cancer risk studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231653PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159218PMC
July 2020

Premenopausal Plasma Osteoprotegerin and Breast Cancer Risk: A Case-Control Analysis Nested within the Nurses' Health Study II.

Cancer Epidemiol Biomarkers Prev 2020 06 10;29(6):1264-1270. Epub 2020 Apr 10.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Background: Emerging evidence supports a role of the receptor activator of NF-κB (RANK) pathway in normal mammary gland development and breast carcinogenesis. Osteoprotegerin (OPG) is the endogenous decoy receptor for RANK-ligand (RANKL), which inhibits RANK-signaling. Whether OPG may be a biomarker of breast cancer risk remains unclear.

Methods: We evaluated the association between plasma OPG and breast cancer risk in a case ( = 297)-control ( = 297) study nested within the Nurses' Health Study II. Cases were women who were cancer-free and premenopausal at blood collection who developed invasive breast cancer. OPG was quantified using an ELISA. Conditional logistic regression was used to estimate multivariable odds ratios (OR) and 95% confidence intervals (CI) for the association between OPG levels and breast cancer risk, adjusting for potential confounders. Unconditional logistic regression, additionally adjusting for matching factors, was used for stratified analyses.

Results: Overall, there was no substantial evidence for an association between plasma OPG levels and breast cancer risk, although the point estimate for the highest (vs. lowest) quartile was below 1 (OR = 0.78; 95% CI, 0.46-1.33; = 0.30). There was no evidence of heterogeneity by various reproductive, hormonal, or tumor characteristics, including hormone receptor status and grade (all ≥ 0.17).

Conclusions: Findings from this prospective study do not provide substantial evidence for an association between circulating OPG and breast cancer risk among premenopausal women; however, we were underpowered in stratified analyses.

Impact: Results do not provide strong evidence for OPG as a potential biomarker of breast cancer risk among premenopausal women.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269832PMC
June 2020

Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer.

Clin Cancer Res 2020 06 13;26(11):2556-2564. Epub 2020 Mar 13.

Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Purpose: Existing cell-free DNA (cfDNA) methods lack the sensitivity needed for detecting minimal residual disease (MRD) following therapy. We developed a test for tracking hundreds of patient-specific mutations to detect MRD with a 1,000-fold lower error rate than conventional sequencing.

Experimental Design: We compared the sensitivity of our approach to digital droplet PCR (ddPCR) in a dilution series, then retrospectively identified two cohorts of patients who had undergone prospective plasma sampling and clinical data collection: 16 patients with ER+/HER2- metastatic breast cancer (MBC) sampled within 6 months following metastatic diagnosis and 142 patients with stage 0 to III breast cancer who received curative-intent treatment with most sampled at surgery and 1 year postoperative. We performed whole-exome sequencing of tumors and designed individualized MRD tests, which we applied to serial cfDNA samples.

Results: Our approach was 100-fold more sensitive than ddPCR when tracking 488 mutations, but most patients had fewer identifiable tumor mutations to track in cfDNA (median = 57; range = 2-346). Clinical sensitivity was 81% ( = 13/16) in newly diagnosed MBC, 23% ( = 7/30) at postoperative and 19% ( = 6/32) at 1 year in early-stage disease, and highest in patients with the most tumor mutations available to track. MRD detection at 1 year was strongly associated with distant recurrence [HR = 20.8; 95% confidence interval, 7.3-58.9]. Median lead time from first positive sample to recurrence was 18.9 months (range = 3.4-39.2 months).

Conclusions: Tracking large numbers of individualized tumor mutations in cfDNA can improve MRD detection, but its sensitivity is driven by the number of tumor mutations available to track.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654718PMC
June 2020

Immunohistochemical analysis of IDH2 R172 hotspot mutations in breast papillary neoplasms: applications in the diagnosis of tall cell carcinoma with reverse polarity.

Mod Pathol 2020 06 2;33(6):1056-1064. Epub 2020 Jan 2.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Tall cell carcinoma with reverse polarity is a rare subtype of breast carcinoma with solid and papillary growth and nuclear features reminiscent of those of the tall cell variant of papillary thyroid carcinoma. These tumors harbor recurrent IDH2 R172 hotspot mutations or TET2 mutations, co-occurring with mutations in PI3K pathway genes. Diagnosis of tall cell carcinomas with reverse polarity is challenging in view of their rarity and the range of differential diagnosis. We sought to determine the sensitivity and specificity of IDH2 R172 immunohistochemistry for the detection of IDH2 R172 hotspot mutations in this entity. We evaluated 14 tall cell carcinomas with reverse polarity (ten excision and five core needle biopsy specimens), 13 intraductal papillomas, 16 solid papillary carcinomas, and 5 encapsulated papillary carcinomas by Sanger sequencing of the IDH2 R172 hotspot locus and of exons 9 and 20 of PIK3CA, and by immunohistochemistry using monoclonal antibodies (11C8B1) to the IDH2 R172S mutation. The 14 tall cell carcinomas with reverse polarity studied harbored IDH2 R172 hotspot mutations, which co-occurred with PIK3CA hotspot mutations in 50% of cases. None of the other papillary neoplasms analyzed displayed IDH2 R172 mutations, however PIK3CA hotspot mutations were detected in 54% of intraductal papillomas, 6% of solid papillary carcinomas, and 20% of encapsulated papillary carcinomas tested. Immunohistochemical analysis with anti-IDH2 R172S antibodies (11C8B1) detected IDH2 R172 mutated protein in 93% (14/15) of tall cell carcinomas with reverse polarity samples including excision (n = 9/10) and core needle biopsy specimens (n = 5), whereas the remaining papillary neoplasms (n = 34) were negative. Our findings demonstrate that immunohistochemical analysis of IDH2 R172 is highly sensitive and specific for the detection of IDH2 R172 hotspot mutations, and likely suitable as a diagnostic tool in the evaluation of excision and core needle biopsy material of tall cell carcinomas with reverse polarity.
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http://dx.doi.org/10.1038/s41379-019-0442-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286791PMC
June 2020

Sexual orientation and benign breast disease in a cohort of U.S. women.

Cancer Causes Control 2020 Feb 1;31(2):173-179. Epub 2020 Jan 1.

Division of Adolescent/Young Adult Medicine, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA.

Purpose: Several studies indicate that sexual minority (e.g., bisexual, lesbian) women may be at an increased risk for breast cancer. However, we know little about how risk factors, such as benign breast disease (BBD)-which can confer nearly a fourfold breast cancer risk increase-may vary across sexual orientation groups.

Methods: Among Nurses' Health Study II participants followed from 1989 to 2013 (n = 99,656), we investigated whether bisexual and lesbian women were more likely than heterosexual women to have breast cancer risk factors including a BBD diagnosis (self-reported biopsy or aspiration confirmed, n = 11,021). Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI).

Results: Compared to heterosexuals, sexual minority participants more commonly reported certain breast cancer risk factors including increased alcohol intake and nulliparity. However, sexual minority participants were more likely than heterosexuals to have certain protective factors including higher body mass index and less oral contraceptive use. When evaluating age- and family history-adjusted rates of BBD diagnoses across sexual orientation groups, bisexual (HR 1.04, 95% CI [0.78, 1.38]) and lesbian (0.99 [0.81, 1.21]) women were just as likely as heterosexuals to have a BBD diagnosis. Results were similar after adjusting for other known breast cancer risk factors.

Conclusions: In this cohort of women across the U.S., sexual minorities were more likely than heterosexuals to have some breast cancer risk factors-including modifiable risk factors such as alcohol intake. Heterosexual, bisexual, and lesbian women were equally as likely to have a BBD diagnosis.
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http://dx.doi.org/10.1007/s10552-019-01258-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981065PMC
February 2020

Prognostic Impact of the 21-Gene Recurrence Score Assay Among Young Women With Node-Negative and Node-Positive ER-Positive/HER2-Negative Breast Cancer.

J Clin Oncol 2020 03 6;38(7):725-733. Epub 2019 Dec 6.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: The 21-gene recurrence score (RS) assay is prognostic among women with early-stage estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer and is used to inform recommendations for chemotherapy. Women ≤ 40 years of age represent a minority of patients studied using gene expression profiles.

Methods: The Young Women's Breast Cancer Study is a prospective cohort of women diagnosed with breast cancer at age ≤ 40 years and enrolled patients between 2006 and 2016 (N = 1,302). We identified patients with stage I-III ER+/HER2- breast cancer. The RS assay was performed on banked specimens for patients who had not been tested clinically. Distant recurrence-free survival (DRFS) was assessed by TAILORx and traditional RS risk groups among patients with axillary node-negative (N0) and limited node-positive (N1) breast cancer.

Results: Among eligible women (N = 577), 189 (33%) had undergone RS testing, and 320 (56%) had banked specimens sufficient for testing. Median follow-up was 6.0 years. Median age at diagnosis was 37.2 years; 300 of 509 patients (59%) had N0 breast cancer, of whom 195 (65%) had an RS of 11-25 and fewer than half (86 of 195; 44%) received chemotherapy. Six-year DRFS rates were 94.4% and 92.3% (RS < 11), 96.9% and 85.2% (RS 11-25), and 85.1% and 71.3% (RS ≥ 26) among women with N0 and N1 disease, respectively.

Conclusion: The RS assay is prognostic among young women with node-negative and limited node-positive breast cancer, representing a valuable tool for risk stratification. Disease outcomes with a median follow-up of 6 years among young women with N0 disease and an RS of 0-25, a minority of whom received chemotherapy, and node-positive disease with an RS < 11 were very good, whereas those with N0 disease and an RS ≥ 26 or N1 disease with an RS ≥ 11 experienced substantial risk of early distant recurrence.
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http://dx.doi.org/10.1200/JCO.19.01959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048163PMC
March 2020

Evaluation of significant genome-wide association studies risk - SNPs in young breast cancer patients.

PLoS One 2019 24;14(5):e0216997. Epub 2019 May 24.

Department of Oncology, Mayo Clinic, Rochester, United States of America.

Purpose: Genome-wide-association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) that are associated with an increased risk of breast cancer. Most of these studies were conducted primarily in postmenopausal breast cancer patients. Therefore, we set out to assess whether or not these breast cancer variants are also associated with an elevated risk of breast cancer in young premenopausal patients.

Methods: In 451 women of European ancestry who had prospectively enrolled in a longitudinal cohort study for women diagnosed with breast cancer at or under age 40, we genotyped 44 SNPs that were previously associated with breast cancer risk. A control group was comprised of 1142 postmenopausal healthy women from the Nurses' Health Study (NHS). We assessed if the frequencies of the adequately genotyped SNPs differed significantly (p≤0.05) between the cohort of young breast cancer patients and postmenopausal controls, and then we corrected for multiple testing.

Results: Genotyping of the controls or cases was inadequate for comparisons between the groups for seven of the 44 SNPs. 9 of the remaining 37 were associated with breast cancer risk in young women with a p-value <0.05: rs10510102, rs1219648, rs13387042, rs1876206, rs2936870, rs2981579, rs3734805, rs3803662 and rs4973768. The directions of these associations were consistent with those in postmenopausal women. However, after correction for multiple testing (Benjamini Hochberg) none of the results remained statistically significant.

Conclusion: After correction for multiple testing, none of the alleles for postmenopausal breast cancer were clearly associated with risk of premenopausal breast cancer in this relatively small study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216997PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534300PMC
January 2020

Parity, breastfeeding, and breast cancer risk by hormone receptor status and molecular phenotype: results from the Nurses' Health Studies.

Breast Cancer Res 2019 03 12;21(1):40. Epub 2019 Mar 12.

Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Ave, Boston, MA, 02115, USA.

Background: Epidemiologic data suggest that parity increases risk of hormone receptor-negative breast cancer and that breastfeeding attenuates this association. Prospective data, particularly on the joint effects of higher parity and breastfeeding, are limited.

Methods: We investigated parity, breastfeeding, and breast cancer risk by hormone-receptor (estrogen (ER) and progesterone receptor (PR)) and molecular subtypes (luminal A, luminal B, HER2-enriched, and basal-like) in the Nurses' Health Study (NHS; 1976-2012) and NHSII (1989-2013). A total of 12,452 (ER+ n = 8235; ER- n = 1978) breast cancers were diagnosed among 199,514 women. We used Cox proportional hazards models, adjusted for breast cancer risk factors, to calculate hazard ratios (HR) and 95% confidence intervals (CI).

Results: Parous women had lower risk of ER+ breast cancer (vs. nulliparous, HR = 0.82 [0.77-0.88]); no association was observed for ER- disease (0.98 [0.84-1.13]; P = 0.03). Among parous women, breastfeeding was associated with lower risk of ER- (vs. never 0.82 [0.74-0.91]), but not ER+, disease (0.99 [0.94-1.05]; P < 0.001). Compared to nulliparous women, higher parity was inversely associated with luminal B breast cancer regardless of breastfeeding (≥ 3 children: ever breastfed, 0.78 [0.62-0.98]; never breastfed, 0.76 [0.58-1.00]) and luminal A disease only among women who had breastfed (≥ 3 children, 0.84 [0.71-0.99]). Basal-like breast cancer risk was suggestively higher among women with higher parity who never breastfed; associations were null among those who ever breastfed.

Conclusions: This study provides evidence that breastfeeding is inversely associated with hormone receptor-negative breast cancers, representing an accessible and cost-effective risk-reduction strategy for aggressive disease subtypes.
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http://dx.doi.org/10.1186/s13058-019-1119-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416887PMC
March 2019

PAM50 Molecular Intrinsic Subtypes in the Nurses' Health Study Cohorts.

Cancer Epidemiol Biomarkers Prev 2019 04 27;28(4):798-806. Epub 2018 Dec 27.

Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.

Background: Modified median and subgroup-specific gene centering are two essential preprocessing methods to assign breast cancer molecular subtypes by PAM50. We evaluated the PAM50 subtypes derived from both methods in a subset of Nurses' Health Study (NHS) and NHSII participants; correlated tumor subtypes by PAM50 with IHC surrogates; and characterized the PAM50 subtype distribution, proliferation scores, and risk of relapse with proliferation and tumor size weighted (ROR-PT) scores in the NHS/NHSII.

Methods: PAM50 subtypes, proliferation scores, and ROR-PT scores were calculated for 882 invasive breast tumors and 695 histologically normal tumor-adjacent tissues. Cox proportional hazards models evaluated the relationship between PAM50 subtypes or ROR-PT scores/groups with recurrence-free survival (RFS) or distant RFS.

Results: PAM50 subtypes were highly comparable between the two methods. The agreement between tumor subtypes by PAM50 and IHC surrogates improved to fair when Luminal subtypes were grouped together. Using the modified median method, our study consisted of 46% Luminal A, 18% Luminal B, 14% HER2-enriched, 15% Basal-like, and 8% Normal-like subtypes; 53% of tumor-adjacent tissues were Normal-like. Women with the Basal-like subtype had a higher rate of relapse within 5 years. HER2-enriched subtypes had poorer outcomes prior to 1999.

Conclusions: Either preprocessing method may be utilized to derive PAM50 subtypes for future studies. The majority of NHS/NHSII tumor and tumor-adjacent tissues were classified as Luminal A and Normal-like, respectively.

Impact: Preprocessing methods are important for the accurate assignment of PAM50 subtypes. These data provide evidence that either preprocessing method can be used in epidemiologic studies.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449178PMC
April 2019

Androgen Receptor Expression and Breast Cancer Survival: Results From the Nurses' Health Studies.

J Natl Cancer Inst 2019 07;111(7):700-708

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.

Background: Hormone receptor signaling is critical in the progression of breast cancers, although the role of the androgen receptor (AR) remains unclear, particularly for estrogen receptor (ER)-negative tumors. This study assessed AR protein expression as a prognostic marker for breast cancer mortality.

Methods: This study included 4147 pre- and postmenopausal women with invasive breast cancer from the Nurses' Health Study (diagnosed 1976-2008) and Nurses' Health Study II (1989-2008) cohorts. AR protein expression was evaluated by immunohistochemistry and scored through pathologist review and as a digitally quantified continuous measure. Hazard ratios (HR) and 95% confidence intervals (CI) of breast cancer mortality were estimated from Cox proportional hazards models, adjusting for patient, tumor, and treatment covariates.

Results: Over a median 16.5 years of follow-up, there were 806 deaths due to breast cancer. In the 7 years following diagnosis, AR expression was associated with a 27% reduction in breast cancer mortality overall (multivariable HR = 0.73, 95% CI = 0.58 to 0.91) a 47% reduction for ER+ cancers (HR = 0.53, 95% CI = 0.41 to 0.69), and a 62% increase for ER- cancers (HR = 1.62, 95% CI = 1.18 to 2.22) (P heterogeneity < .001). A log-linear association was observed between AR expression and breast cancer mortality among ER- cancers (HR = 1.14, 95% CI = 1.02 to 1.26 per each 10% increase in AR), although no log-linear association was observed among ER+ cancers.

Conclusions: AR expression was associated with improved prognosis in ER+ tumors and worse prognosis in ER- tumors in the first 5-10 years postdiagnosis. These findings support the continued evaluation of AR-targeted therapies for AR+/ER- breast cancers.
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http://dx.doi.org/10.1093/jnci/djy173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624168PMC
July 2019

Does mammographic density mediate risk factor associations with breast cancer? An analysis by tumor characteristics.

Breast Cancer Res Treat 2018 Jul 3;170(1):129-141. Epub 2018 Mar 3.

Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.

Background: Though mammographic density (MD) has been proposed as an intermediate marker of breast cancer risk, few studies have examined whether the associations between breast cancer risk factors and risk are mediated by MD, particularly by tumor characteristics.

Methods: Our study population included 3392 cases (1105 premenopausal) and 8882 (3192 premenopausal) controls from four case-control studies. For established risk factors, we estimated the percent of the total risk factor association with breast cancer that was mediated by percent MD (secondarily, by dense area and non-dense area) for invasive breast cancer as well as for subtypes defined by the estrogen receptor (ER+/ER-), progesterone receptor (PR+/PR-), and HER2 (HER2+/HER2-). Analyses were conducted separately in pre- and postmenopausal women.

Results: Positive associations between prior breast biopsy and risk of invasive breast cancer as well as all subtypes were partially mediated by percent MD in pre- and postmenopausal women (percent mediated = 11-27%, p ≤ 0.02). In postmenopausal women, nulliparity and hormone therapy use were positively associated with invasive, ER+ , PR+ , and HER2- breast cancer; percent MD partially mediated these associations (percent mediated ≥ 31%, p ≤ 0.02). Further, among postmenopausal women, percent MD partially mediated the positive association between later age at first birth and invasive as well as ER+ breast cancer (percent mediated = 16%, p ≤ 0.05).

Conclusion: Percent MD partially mediated the associations between breast biopsy, nulliparity, age at first birth, and hormone therapy with risk of breast cancer, particularly among postmenopausal women, suggesting that these risk factors at least partially influence breast cancer risk through changes in breast tissue composition.
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http://dx.doi.org/10.1007/s10549-018-4735-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994184PMC
July 2018

Contemporary Topics in Breast Pathology.

Authors:
Laura C Collins

Surg Pathol Clin 2018 Mar 18;11(1):ix. Epub 2017 Dec 18.

Vice Chair of Anatomic Pathology, Director of Breast Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA. Electronic address:

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http://dx.doi.org/10.1016/j.path.2017.12.001DOI Listing
March 2018
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