Person: Collins, Laura
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Collins
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Laura
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Collins, Laura
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Publication Alcohol Intake Between Menarche and First Pregnancy: A Prospective Study of Breast Cancer Risk(Oxford University Press, 2013) Liu, Ying; Colditz, Graham; Rosner, Bernard; Berkey, Catherine; Collins, Laura; Schnitt, Stuart; Connolly, James; Chen, Wendy; Willett, Walter; Tamimi, RullaBackground: Adult alcohol consumption during the previous year is related to breast cancer risk. Breast tissue is particularly susceptible to carcinogens between menarche and first full-term pregnancy. No study has characterized the contribution of alcohol consumption during this interval to risks of proliferative benign breast disease (BBD) and breast cancer. Methods: We used data from 91005 parous women in the Nurses’ Health Study II who had no cancer history, completed questions on early alcohol consumption in 1989, and were followed through June 30, 2009, to analyze breast cancer risk. A subset of 60093 women who had no history of BBD or cancer in 1991 and were followed through June 30, 2001, were included in the analysis of proliferative BBD. Relative risks (RRs) were estimated using Cox proportional hazard regression. Results: We identified 1609 breast cancer cases and 970 proliferative BBD cases confirmed by central histology review. Alcohol consumption between menarche and first pregnancy, adjusted for drinking after first pregnancy, was associated with risks of breast cancer (RR = 1.11 per 10g/day intake; 95% confidence interval [CI] = 1.00 to 1.23) and proliferative BBD (RR = 1.16 per 10g/day intake; 95% CI = 1.02 to 1.32). Drinking after first pregnancy had a similar risk for breast cancer (RR = 1.09 per 10g/day intake; 95% CI = 0.96 to 1.23) but not for BBD. The association between drinking before first pregnancy and breast neoplasia appeared to be stronger with longer menarche to first pregnancy intervals. Conclusions: Alcohol consumption before first pregnancy was consistently associated with increased risks of proliferative BBD and breast cancer.Publication Estrogen receptor negative/progesterone receptor positive breast cancer is not a reproducible subtype(BioMed Central, 2013) Hefti, Marco; Hu, Rong; Knoblauch, Nicholas W; Collins, Laura; Haibe-Kains, Benjamin; Tamimi, Rulla; Beck, AndrewIntroduction: Estrogen receptor (ER) and progesterone receptor (PR) testing are performed in the evaluation of breast cancer. While the clinical utility of ER as a predictive biomarker to identify patients likely to benefit from hormonal therapy is well-established, the added value of PR is less well-defined. The primary goals of our study were to assess the distribution, inter-assay reproducibility, and prognostic significance of breast cancer subtypes defined by patterns of ER and PR expression. Methods: We integrated gene expression microarray (GEM) and clinico-pathologic data from 20 published studies to determine the frequency (n = 4,111) and inter-assay reproducibility (n = 1,752) of ER/PR subtypes (ER+/PR+, ER+/PR-, ER-/PR-, ER-/PR+). To extend our findings, we utilized a cohort of patients from the Nurses’ Health Study (NHS) with ER/PR data recorded in the medical record and assessed on tissue microarrays (n = 2,011). In both datasets, we assessed the association of ER and PR expression with survival. Results: In a genome-wide analysis, progesterone receptor was among the least variable genes in ER- breast cancer. The ER-/PR+ subtype was rare (approximately 1 to 4%) and showed no significant reproducibility (Kappa = 0.02 and 0.06, in the GEM and NHS datasets, respectively). The vast majority of patients classified as ER-/PR+ in the medical record (97% and 94%, in the GEM and NHS datasets) were re-classified by a second method. In the GEM dataset (n = 2,731), progesterone receptor mRNA expression was associated with prognosis in ER+ breast cancer (adjusted P <0.001), but not in ER- breast cancer (adjusted P = 0.21). PR protein expression did not contribute significant prognostic information to multivariate models considering ER and other standard clinico-pathologic features in the GEM or NHS datasets. Conclusion: ER-/PR+ breast cancer is not a reproducible subtype. PR expression is not associated with prognosis in ER- breast cancer, and PR does not contribute significant independent prognostic information to multivariate models considering ER and other standard clinico-pathologic factors. Given that PR provides no clinically actionable information in ER+ breast cancer, these findings question the utility of routine PR testing in breast cancer.Publication Digital Quantification of Gene Expression in Sequential Breast Cancer Biopsies Reveals Activation of an Immune Response(Public Library of Science, 2013) Jeselsohn, Rinath; Werner, Lillian; Regan, Meredith; Fatima, Aquila; Gilmore, Lauren; Collins, Laura; Beck, Andrew; Bailey, Shannon T.; He, Housheng Hansen; Buchwalter, Gilles; Brown, Myles; Iglehart, J. Dirk; Richardson, Andrea; Come, StevenAdvancements in molecular biology have unveiled multiple breast cancer promoting pathways and potential therapeutic targets. Large randomized clinical trials remain the ultimate means of validating therapeutic efficacy, but they require large cohorts of patients and are lengthy and costly. A useful approach is to conduct a window of opportunity study in which patients are exposed to a drug pre-surgically during the interval between the core needle biopsy and the definitive surgery. These are non-therapeutic studies and the end point is not clinical or pathological response but rather evaluation of molecular changes in the tumor specimens that can predict response. However, since the end points of the non-therapeutic studies are biologic, it is critical to first define the biologic changes that occur in the absence of treatment. In this study, we compared the molecular profiles of breast cancer tumors at the time of the diagnostic biopsy versus the definitive surgery in the absence of any intervention using the Nanostring nCounter platform. We found that while the majority of the transcripts did not vary between the two biopsies, there was evidence of activation of immune related genes in response to the first biopsy and further investigations of the immune changes after a biopsy in early breast cancer seem warranted.Publication Crowdsourcing scoring of immunohistochemistry images: Evaluating Performance of the Crowd and an Automated Computational Method(Nature Publishing Group, 2017) Irshad, Humayun; Oh, Eun-Yeong; Schmolze, Daniel; Quintana, Liza; Collins, Laura; Tamimi, Rulla; Beck, AndrewThe assessment of protein expression in immunohistochemistry (IHC) images provides important diagnostic, prognostic and predictive information for guiding cancer diagnosis and therapy. Manual scoring of IHC images represents a logistical challenge, as the process is labor intensive and time consuming. Since the last decade, computational methods have been developed to enable the application of quantitative methods for the analysis and interpretation of protein expression in IHC images. These methods have not yet replaced manual scoring for the assessment of IHC in the majority of diagnostic laboratories and in many large-scale research studies. An alternative approach is crowdsourcing the quantification of IHC images to an undefined crowd. The aim of this study is to quantify IHC images for labeling of ER status with two different crowdsourcing approaches, image-labeling and nuclei-labeling, and compare their performance with automated methods. Crowdsourcing- derived scores obtained greater concordance with the pathologist interpretations for both image-labeling and nuclei-labeling tasks (83% and 87%), as compared to the pathologist concordance achieved by the automated method (81%) on 5,338 TMA images from 1,853 breast cancer patients. This analysis shows that crowdsourcing the scoring of protein expression in IHC images is a promising new approach for large scale cancer molecular pathology studies.Publication Postmenopausal mammographic breast density and subsequent breast cancer risk according to selected tissue markers(Nature Publishing Group, 2015) Yaghjyan, Lusine; Pettersson, Andreas; Colditz, Graham A; Collins, Laura; Schnitt, Stuart; Beck, Andrew; Rosner, Bernard; Vachon, Celine; Tamimi, RullaBackground: This study aimed to determine if associations of pre-diagnostic percent breast density, absolute dense area, and non-dense area with subsequent breast cancer risk differ by the tumour's molecular marker status. Methods: We included 1010 postmenopausal women with breast cancer and 2077 matched controls from the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHS II) cohorts. Breast density was estimated from digitised film mammograms using computer-assisted thresholding techniques. Information on breast cancer risk factors was obtained prospectively from biennial questionnaires. Polychotomous logistic regression was used to assess associations of breast density measures with tumour subtypes by the status of selected tissue markers. All tests of statistical significance were two sided. Results: The association of percent density with breast cancer risk appeared to be stronger in ER− as compared with ER+ tumours, but the difference did not reach statistical significance (density ⩾50% vs <10% odds ratio (OR)=3.06, 95% confidence interval (CI) 2.17–4.32 for ER+ OR=4.61, 95% CI 2.36–9.03 for ER−, Pheterogeneity=0.08). Stronger positive associations were found for absolute dense area and CK5/6− and EGFR− as compared with respective marker-positive tumours (Pheterogeneity=0.002 and 0.001, respectively). Stronger inverse associations of non-dense area with breast cancer risk were found for ER− as compared with ER+ tumours (Pheterogeneity=0.0001) and for AR+, CK5/6+, and EGFR+ as compared with respective marker-negative tumours (Pheterogeneity=0.03, 0.005, and 0.009, respectively). The associations of density measures with breast cancer did not differ by progesterone receptor and human epidermal growth factor receptor 2 status. Conclusions: Breast density influences the risk of breast cancer subtypes by potentially different mechanisms.Publication Expression of estrogen receptor, progesterone receptor, and Ki67 in normal breast tissue in relation to subsequent risk of breast cancer(2016) Oh, Hannah; Eliassen, A; Wang, Molin; Smith-Warner, Stephanie; Beck, Andrew; Schnitt, Stuart; Collins, Laura; Connolly, James; Montaser-Kouhsari, Laleh; Polyak, Kornelia; Tamimi, RullaAlthough expression of estrogen receptor (ER), progesterone receptor (PR), and cell proliferation marker Ki67 serve as predictive and prognostic factors in breast cancers, little is known about their roles in normal breast tissue. Here in a nested case–control study within the Nurses’ Health Studies (90 cases, 297 controls), we evaluated their expression levels in normal breast epithelium in relation to subsequent breast cancer risk among women with benign breast disease. Tissue microarrays were constructed using cores obtained from benign biopsies containing normal terminal duct lobular units and immunohistochemical stained for these markers. We found PR and Ki67 expression was non-significantly but positively associated with subsequent breast cancer risk, whereas ER expression was non-significantly inversely associated. After stratifying by lesion subtype, Ki67 was significantly associated with higher risk among women with proliferative lesions with atypical hyperplasia. However, given the small sample size, further studies are required to confirm these results.Publication Insulin-like growth factor-1, insulin-like growth factor binding protein-3 and lobule type in the Nurses' Health Study II(BioMed Central, 2012) Rice, Megan; Tamimi, Rulla; Connolly, James; Collins, Laura; Shen, Dejun; Pollak, Michael N; Rosner, Bernard; Hankinson, Susan; Tworoger, ShelleyIntroduction: Previous research in the Nurses' Health Study (NHS) and the NHSII observed that, among women diagnosed with benign breast disease (BBD), those with predominant type 1/no type 3 lobules (a marker of complete involution) versus other lobule types were at lower risk of subsequent breast cancer. Studies in animal models suggest that insulin-like growth factor-1 (IGF-1) may inhibit involution of lobules in the breast; however, this has not been studied in humans. Methods: We conducted a cross-sectional study among 472 women in the NHSII who were diagnosed with biopsy-confirmed proliferative BBD between 1991 and 2002 and provided blood samples between 1996 and 1999. A pathologist, blinded to exposure status, classified lobule type in normal adjacent tissue on available biopsy slides according to the number of acini per lobule. For each participant, the pathologist determined the predominant lobule type (that is, type 1, type 2, or type 3) and whether any type 1 or any type 3 lobules were present. Lobule type was then classified as: predominant type 1/no type 3 lobules, which is suggestive of complete involution; or other lobule types. Multivariate logistic models were used to assess the associations between plasma IGF-1, insulin-like growth factor binding protein-3 (IGFBP-3), and the ratio of IGF-1:IGFBP-3 levels with lobule type. Results: In univariate analyses, greater age, higher body mass index, postmenopausal status, nulliparity, and lower IGF-1 levels were associated with predominant type 1/no type 3 lobules (P < 0.05). In multivariate models adjusting for age and assay batch, higher IGF-1 levels were associated with decreased odds of predominant type 1/no type 3 lobules (odds ratio quartile 4 vs. quartile 1 = 0.37, 95% confidence interval = 0.15 to 0.89). Greater ratios of IGF-1:IGFBP-3 levels were also associated with decreased odds of predominant type 1/no type 3 lobules (odds ratio quartile 4 vs. quartile 1 = 0.26, 95% confidence interval = 0.11 to 0.64). These results were slightly attenuated after adjustment for other potential predictors of lobule type. Conclusions: Higher IGF-1 levels and a greater IGF-1:IGFBP-3 ratio were associated with decreased odds of having predominant type 1 lobules/no type 3 lobules among women with proliferative BBD in the NHSII. This study provides further evidence for the role of insulin-like growth factors in the structure of breast lobules and lobular involution.Publication Columnar Cell Lesions and Subsequent Breast Cancer Risk: A Nested Case-Control Study(BioMed Central, 2010) Aroner, Sarah A.; Collins, Laura; Schnitt, Stuart; Connolly, James; Colditz, Graham; Tamimi, RullaIntroduction: Histologic and genetic evidence suggests that at least some columnar cell lesions (CCL) of the breast represent precursor lesions in the low-grade breast neoplasia pathway. However, the risk of subsequent breast cancer associated with the presence of CCL in a benign breast biopsy is poorly understood.Methods The authors examined the association between the presence of CCL and subsequent breast cancer risk in a nested case-control study of benign breast disease (BBD) and breast cancer within the Nurses' Health Studies (394 cases, 1,606 controls). Benign breast biopsy slides were reviewed by pathologists and CCL presence assessed. Logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for the association between CCL and breast cancer risk. Results: Women with CCL (140 cases, 448 controls) had an increased risk of breast cancer compared with those without CCL (OR = 1.44, 95% CI: 1.14 to 1.83), although this was attenuated and became non-significant after adjustment for the histologic category of BBD (OR = 1.20, 95% CI: 0.94 to 1.54). CCL presence was associated with the greatest risk of breast cancer for those with nonproliferative BBD (OR = 1.36, 95% CI: 0.79 to 2.37) and the lowest risk for those with atypical hyperplasia (AH) (OR = 1.10, 95% CI: 0.65 to 1.87); however, this apparent heterogeneity in risk across BBD categories was not significant (P for interaction between CCL presence and BBD category = 0.77). Conclusions: These results provide evidence that CCL may be an important marker of breast cancer risk in women with BBD but suggest that CCL do not increase breast cancer risk independently of concurrent proliferative changes in the breast.Publication Luminal B Breast Tumors Are Not HER2 Positive – Authors' Response(BioMed Central, 2008) Tamimi, Rulla; Schnitt, Stuart; Colditz, Graham; Collins, LauraPublication Comparison of Molecular Phenotypes of Ductal Carcinoma In Situ and Invasive Breast Cancer(BioMed Central, 2008) Tamimi, Rulla; Baer, Heather; Marotti, Jonathan; Galan, Mark; Galaburda, Laurie; Fu, Yineng; Deitz, Anne C; Connolly, James; Schnitt, Stuart; Colditz, Graham; Collins, LauraIntroduction: At least four major categories of invasive breast cancer that are associated with different clinical outcomes have been identified by gene expression profiling: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) and basal-like. However, the prevalence of these phenotypes among cases of ductal carcinoma in situ (DCIS) has not been previously evaluated in detail. The purpose of this study was to compare the prevalence of these distinct molecular subtypes among cases of DCIS and invasive breast cancer. Methods: We constructed tissue microarrays (TMAs) from breast cancers that developed in 2897 women enrolled in the Nurses' Health Study (1976 to 1996). TMA slides were immunostained for oestrogen receptor (ER), progesterone receptor (PR), HER2, cytokeratin 5/6 (CK5/6) and epidermal growth factor receptor (EGFR). Using these immunostain results, cases were grouped into molecularly defined subtypes. Results: The prevalence of the distinct molecular phenotypes differed significantly between DCIS (n = 272) and invasive breast cancers (n = 2249). The luminal A phenotype was significantly more frequent among invasive cancers (73.4%) than among DCIS lesions (62.5%) (p = 0.0002). In contrast, luminal B and HER2 molecular phenotypes were both more frequent among DCIS (13.2% and 13.6%, respectively) as compared with invasive tumours (5.2% and 5.7%, respectively) (p < 0.0001). The basal-like phenotype was more frequent among the invasive cancers (10.9%) than DCIS (7.7%), although this difference was not statistically significant (p = 0.15). High-grade DCIS and invasive tumours were more likely to be HER2 type and basal-like than low- or intermediate-grade lesions. Among invasive tumours, basal-like and HER2 type tumours were more likely to be more than 2 cm in size, high-grade and have nodal involvement compared with luminal A tumours. Conclusion: The major molecular phenotypes previously identified among invasive breast cancers were also identified among cases of DCIS. However, the prevalence of the luminal A, luminal B and HER2 phenotypes differed significantly between DCIS and invasive breast cancers.