Effect of testosterone therapy on breast tissue composition and mammographic breast density in trans masculine individuals.

BACKGROUND: The effect of gender-affirming testosterone therapy (TT) on breast cancer risk is unclear. This study investigated the association between TT and breast tissue composition and breast tissue density in trans masculine individuals (TMIs). METHODS: Of the 444 TMIs who underwent chest-contouring surgeries between 2013 and 2019, breast tissue composition was assessed in 425 TMIs by the pathologists (categories of lobular atrophy and stromal composition) and using our automated deep-learning algorithm (% epithelium, % fibrous stroma, and % fat). Forty-two out of 444 TMIs had mammography prior to surgery and their breast tissue density was read by a radiologist. Mammography digital files, available for 25/42 TMIs, were analyzed using the LIBRA software to obtain percent density, absolute dense area, and absolute non-dense area. Linear regression was used to describe the associations between duration of TT use and breast tissue composition or breast tissue density measures, while adjusting for potential confounders. Analyses stratified by body mass index were also conducted. RESULTS: Longer duration of TT use was associated with increasing degrees of lobular atrophy (p < 0.001) but not fibrous content (p = 0.82). Every 6 months of TT was associated with decreasing amounts of epithelium (exp(ß) = 0.97, 95% CI 0.95,0.98, adj p = 0.005) and fibrous stroma (exp(ß) = 0.99, 95% CI 0.98,1.00, adj p = 0.05), but not fat (exp(ß) = 1.01, 95%CI 0.98,1.05, adj p = 0.39). The effect of TT on breast epithelium was attenuated in overweight/obese TMIs (exp(ß) = 0.98, 95% CI 0.95,1.01, adj p = 0.14). When comparing TT users versus non-users, TT users had 28% less epithelium (exp(ß) = 0.72, 95% CI 0.58,0.90, adj p = 0.003). There was no association between TT and radiologist's breast density assessment (p = 0.58) or LIBRA measurements (p > 0.05). CONCLUSIONS: TT decreases breast epithelium, but this effect is attenuated in overweight/obese TMIs. TT has the potential to affect the breast cancer risk of TMIs. Further studies are warranted to elucidate the effect of TT on breast density and breast cancer risk.

Association of early menarche with breast tumor molecular features and recurrence.

BACKGROUND: Early menarche is an established risk factor for breast cancer but its molecular contribution to tumor biology and prognosis remains unclear. METHODS: We profiled transcriptome-wide gene expression in breast tumors (N = 846) and tumor-adjacent normal tissues (N = 666) from women in the Nurses' Health Studies (NHS) to investigate whether early menarche (age < 12) is associated with tumor molecular and prognostic features in women with breast cancer. Multivariable linear regression and pathway analyses using competitive gene set enrichment analysis were conducted in both tumor and adjacent-normal tissue and externally validated in TCGA (N = 116). Subgroup analyses stratified on ER-status based on the tumor were also performed. PAM50 signatures were used for tumor molecular subtyping and to generate proliferation and risk of recurrence scores. We created a gene expression score using LASSO regression to capture early menarche based on 28 genes from FDR-significant pathways in breast tumor tissue in NHS and tested its association with 10-year disease-free survival in both NHS (N = 836) and METABRIC (N = 952). RESULTS: Early menarche was significantly associated with 369 individual genes in adjacent-normal tissues implicated in extracellular matrix, cell adhesion, and invasion (FDR ≤ 0.1). Early menarche was associated with upregulation of cancer hallmark pathways (18 significant pathways in tumor, 23 in tumor-adjacent normal, FDR ≤ 0.1) related to proliferation (e.g. Myc, PI3K/AKT/mTOR, cell cycle), oxidative stress (e.g. oxidative phosphorylation, unfolded protein response), and inflammation (e.g. pro-inflammatory cytokines IFN α and IFN γ ). Replication in TCGA confirmed these trends. Early menarche was associated with significantly higher PAM50 proliferation scores (ß = 0.082 [0.02-0.14]), odds of aggressive molecular tumor subtypes (basal-like, OR = 1.84 [1.18-2.85] and HER2-enriched, OR = 2.32 [1.46-3.69]), and PAM50 risk of recurrence score (ß = 4.81 [1.71-7.92]). Our NHS-derived early menarche gene expression signature was significantly associated with worse 10-year disease-free survival in METABRIC (N = 952, HR = 1.58 [1.10-2.25]). CONCLUSIONS: Early menarche is associated with more aggressive molecular tumor characteristics and its gene expression signature within tumors is associated with worse 10-year disease-free survival among women with breast cancer. As the age of onset of menarche continues to decline, understanding its relationship to breast tumor characteristics and prognosis may lead to novel secondary prevention strategies.

Associations of stem cell markers CD44, CD24 and ALDH1A1 with mammographic breast density in women with benign breast biopsies.

BACKGROUND: We examined associations of CD44, CD24 and ALDH1A1 breast stem cell markers with mammographic breast density (MBD), a well-established breast cancer (BCa) risk factor. METHODS: We included 218 cancer-free women with biopsy-confirmed benign breast disease within the Nurses' Health Study (NHS) and NHSII. The data on BCa risk factors were obtained from biennial questionnaires. Immunohistochemistry (IHC) was done on tissue microarrays. For each core, the IHC expression was assessed using a semi-automated platform and expressed as percent of positively stained cells for each marker out of the total cell count. MBD was assessed with computer-assisted techniques. Generalised linear regression was used to examine the associations of each marker with square root-transformed percent density (PD), absolute dense and non-dense areas (NDA), adjusted for BCa risk factors. RESULTS: Stromal CD44 and ALDH1A1 expression was positively associated with PD (≥ 10% vs. <10% ß = 0.56, 95% confidence interval [CI] [0.06; 1.07] and ß = 0.81 [0.27; 1.34], respectively) and inversely associated with NDA (ß per 10% increase = -0.17 [-0.34; -0.01] and ß for ≥10% vs. <10% = -1.17 [-2.07; -0.28], respectively). Epithelial CD24 expression was inversely associated with PD (ß per 10% increase = -0.14 [-0.28; -0.01]. Stromal and epithelial CD24 expression was positively associated with NDA (ß per 10% increase = 0.35 [0.2 × 10-2; 0.70] and ß per 10% increase = 0.34 [0.11; 0.57], respectively). CONCLUSION: Expression of stem cell markers is associated with MBD.

Associations of Early-Life and Adult Anthropometric Measures with the Expression of Stem Cell Markers CD44, CD24, and ALDH1A1 in Women with Benign Breast Biopsies.

BACKGROUND: According to the stem cell hypothesis, breast carcinogenesis may be related to the breast stem cell pool size. However, little is known about associations of breast cancer risk factors, such as anthropometric measures, with the expression of stem cell markers in noncancerous breast tissue. METHODS: The analysis included 414 women with biopsy-confirmed benign breast disease in the Nurses' Health Study and Nurses' Health Study II. Birthweight, weight at age 18, current weight, and current height were reported via self-administered questionnaires. IHC staining of stem cell markers (CD44, CD24, and aldehyde dehydrogenase family 1 member A1) in histopathologically normal epithelial and stromal breast tissue was quantified using an automated computational image analysis system. Linear regression was used to examine the associations of early-life and adult anthropometric measures with log-transformed stem cell marker expression, adjusting for potential confounders. RESULTS: Birthweight [≥10.0 vs. <5.5 lbs: ß (95% confidence interval) = 4.29 (1.02, 7.56); P trend = 0.001 in the stroma] and adult height [≥67.0 vs. <63.0 inch: 0.86 (0.14, 1.58); P trend = 0.02 in the epithelium and stroma combined] were positively associated with CD44 expression. Childhood body fatness was inversely associated (P trend = 0.03) whereas adult height was positively associated with CD24 expression in combined stroma and epithelium (P trend = 0.03). CONCLUSIONS: Our data suggest that anthropometric measures, such as birthweight, adult height, and childhood body fatness, may be associated with the stem cell expression among women with benign breast disease. IMPACT: Anthropometric measures, such as birthweight, height, and childhood body fatness, may have long-term impacts on stem cell population in the breast.

Associations of reproductive breast cancer risk factors with expression of stem cell markers in benign breast tissue.

Background: We investigated the associations of reproductive factors known to influence breast cancer risk with the expression of breast stem cell markers CD44, CD24, and ALDH1A1 in benign breast biopsy samples. Methods: We included 439 cancer-free women with biopsy-confirmed benign breast disease within the Nurses' Health Study (NHS) and NHSII. The data on reproductive and other breast cancer risk factors were obtained from biennial questionnaires. Immunohistochemistry (IHC) was performed on tissue microarrays. For each core, the IHC expression was assessed using a semi-automated platform and expressed as % of cells that stained positive for a specific marker out of the total cell count. Generalized linear regression was used to examine the associations of reproductive factors with a log-transformed expression of each marker (in epithelium and stroma), adjusted for other breast cancer risk factors. Results: In multivariate analysis, the time between menarche and age at first birth was inversely associated with CD44 in epithelium (ß per 5 years = -0.38, 95% CI -0.69; -0.06). Age at first birth and the time between menarche and age at first birth were inversely associated with ALDH1A1 (stroma: ß per 5 years = -0.43, 95% CI -0.76; -0.10 and ß = -0.47, 95% CI -0.79; -0.15, respectively; epithelium: ß = -0.15, 95% CI -0.30; -0.01 and ß = -0.17, 95% CI -0.30; -0.03, respectively). Time since last pregnancy was inversely associated with stromal ALDH1A1 (ß per 5 years = -0.55, 95% CI -0.98; -0.11). No associations were found for CD24. The observed associations were similar in premenopausal women. In postmenopausal women, lifetime duration of breastfeeding was inversely associated with stromal ALDH1A1 expression (ß for ≥24 vs. 0 to <1 months = -2.24, 95% CI 3.96; -0.51, p-trend = 0.01). Conclusion: Early-life reproductive factors may influence CD44 and ALDH1A1 expression in benign breast tissue.

Effect of testosterone therapy on breast tissue composition and mammographic breast density in trans masculine individuals.

Objective: Determine the association between TT and breast tissue composition and breast tissue density in trans masculine individuals (TMIs). Design: This is a cross-sectional study. Setting: TMIs (n=444) underwent chest-contouring surgeries to treat their gender dysphoria between 2013 and 2019 at an urban medical center. Participants: Of the 444 TMIs, 425 had pathology images analyzed by our deep-learning algorithm to extract breast tissue composition. A subset of 42/444 TMIs had mammography prior to surgery; mammography files were available for 25/42 TMIs and analyzed using a breast density software, LIBRA. Main Outcomes and Measures: The first outcome was the association of duration of TT and breast tissue composition assessed by pathologists (categories of lobular atrophy and stromal composition) or by our algorithm (% epithelium, % fibrous stroma, and % fat). The second outcome is the association of TT and breast density as assessed by a radiologist (categorical variable) or by LIBRA (percent density, absolute dense area, and absolute non-dense area). Results: Length of TT was associated with increasing degrees of lobular atrophy ( p <0.001) but not fibrous content ( p =0.821) when assessed by the pathologists. Every six months of TT was associated with decreased amounts of both epithelium (exp(ß)=0.97, 95% CI 0.95-0.98, adj p =0.005) and stroma (exp(ß)=0.99, 95% CI 0.98-1.00, adj p =0.051), but not fat (exp(ß)=1.01, 95%CI 0.98-1.05, p =0.394) in fully adjusted models. There was no association between TT and radiologist's breast density assessment ( p =0.575) or LIBRA measurements ( p >0.05). Conclusions: TT decreases breast epithelium and fibrous stroma, thus potentially reducing the breast cancer risk of TMIs. Further studies are warranted to elucidate the effect of TT on breast density and breast cancer risk. Summary Box: Very little is known about the effect of gender-affirming testosterone therapy on cancer risks, such as breast cancer.Epidemiological studies had different conclusions about the association between testosterone and breast cancer in cisgender women (positive association) and trans masculine individuals (inverse association).More laboratory-based research are needed to understand the effect of testosterone on breast cancer risk in the understudied trans masculine population.Our study provides quantitative histological evidence to support prior epidemiological reports that testosterone may reduce breast cancer risk in trans masculine individuals.

Underrepresented Groups and Perceived Educational Barriers for Residency and Fellowship Success.

BACKGROUND: The study aimed to compare barriers perceived by medical students and resident physicians identifying as of underrepresented groups in medicine (UIM) and/or as sexual and gender minorities (SGM) to individuals not identifying with these groups, especially for trainees with an interest in dermatology. METHODS: Cross-sectional survey of medical students and resident physicians based in the United States from February 2021 to July 2021, with subgroup analysis of trainees with interest in dermatology. FINDINGS: Among trainees interested in dermatology, the most notable barriers for the UIM group were 1) lack of home program in specialty/fellowship of interest (4.71±1.73); 2) lack of connections/networking opportunities (4.14±1.29); 3) lack of opportunity to obtain AOA membership (4.00±1.96); 4) obtaining mentorship (4.00±1.47); and lack of diversity in specialty/fellowship of interest (3.93±1.14). CONCLUSIONS AND RELEVANCE: Increasing focused mentorship programs and fostering environments that embrace diversity are key to reducing perceived barriers for minority candidates. J Drugs Dermatol. 2023;22(12):1210-1215. doi:10.36849/JDD.7528R1.

Perceived Barriers to Career Advancement: Medical Students and Resident Physicians.

BACKGROUND: The path to becoming a physician is challenging, with various barriers influencing medical student and resident physician residency and fellowship training career decisions. Studies comparing perceived obstacles at disparate training levels are limited and given these obstacles are dynamic, studies are frequently needed to evaluate perceived barriers to pursuing residency specialty or fellowship of interest for physician trainees. OBJECTIVE: To evaluate and compare perceived barriers to obtaining residency specialty or fellowship of choice for medical students and resident physicians, respectively. METHODS: A Likert scale survey assessing perceived barriers was administered via the listservs of medical schools and organizations in 2021. Differences in the Likert scale score mean between medical students and resident physicians were measured with student t-tests (2-sided). RESULTS: A total of 404 medical trainees participated (301 medical students and 103 resident physicians). Medical students indicated lack of opportunity to obtain alpha omega alpha membership as the most crucial perceived barrier (mean Likert scale score ± standard deviation, 4.01±1.97), followed by USMLE Step 1 score (3.92±1.89) and lack of home program in specialty/fellowship of interest (3.62±1.85). Similarly, resident physicians implicated the lack of a home program in a specialty/fellowship of interest as the most prominent barrier (3.48±1.78), followed by lack of connections/networking (3.17±1.50) and probability of matching (3.14±1.44). CONCLUSIONS: The lack of a home program was an important barrier to pursuing a specialty or fellowship of choice for both medical students and resident physicians, respectively, and may have been heightened during the COVID-19 pandemic. J Drugs Dermatol. 2023;22(11):e17-e20    doi:10.36849/JDD.7005e.

Invasive Ductal Carcinoma of the Breast in a Transgender Man: A Case Report.

There is limited literature about breast cancer in the transgender population. Very little is known about how gender-affirming hormone therapy affects their breast cancer risk. On the other end, for those diagnosed with breast cancer, there are no clinical guidelines to manage their breast cancer, specifically, how to manage their gender-affirming hormone therapy during breast cancer treatment. Here, we report a 52-year-old transman diagnosed with a grade 2 invasive ductal carcinoma (ER+/PR+/HER2-), and ductal carcinoma in situ (DCIS) of intermediate grade. We discussed his risk factors as well as treatment options.

Toker Cell Hyperplasia in the Nipple-Areolar Complex of Transmasculine Individuals.

We previously reported breast histopathologic features associated with testosterone therapy in transmasculine chest-contouring surgical specimens. During that study, we observed a high frequency of intraepidermal glands in the nipple-areolar complex (NAC) formed by Toker cells. This study reports Toker cell hyperplasia (TCH)-the presence of clusters of Toker cells consisting of at least 3 contiguous cells and/or glands with lumen formation-in the transmasculine population. Increased numbers of singly dispersed Toker cells were not considered TCH. Among the 444 transmasculine individuals, 82 (18.5%) had a portion of their NAC excised and available for evaluation. We also reviewed the NACs from 55 cisgender women who were aged <50 years old and had full mastectomies. The proportion of transmasculine cases with TCH (20/82; 24.4%) was 1.7-fold higher than cisgender women (8/55; 14.5%) but did not achieve significance (P = .20). However, in cases with TCH, the rate of gland formation is 2.4-fold higher in transmasculine cases, achieving borderline significance (18/82 vs 5/55; P = .06). Among transmasculine individuals, TCH was significantly more likely to be present in those with higher body mass index (P = .03). A subset of 5 transmasculine and 5 cisgender cases were stained for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), androgen receptor (AR), cytokeratin 7, and Ki67. All 10 cases were cytokeratin 7+ and Ki67-; 9 out of 10 cases were AR+. Toker cells in transmasculine cases demonstrated variable expression of ER, PR, and HER2. For cisgender cases, Toker cells were consistently ER+, PR-, and HER2-. In conclusion, there is a higher rate of TCH in the transmasculine than cisgender population, particularly among transmasculine individuals with high body mass index and taking testosterone. To our knowledge, this is the first study to demonstrate that Toker cells are AR+. Toker cell features display variable ER, PR, and HER2 immunoreactivity. The clinical significance of TCH in the transmasculine population remains to be elucidated.

Associations of alcohol consumption with breast tissue composition.

BACKGROUND: We investigated the associations of alcohol with percentage of epithelium, stroma, fibroglandular tissue (epithelium + stroma), and fat in benign breast biopsy samples. METHODS: We included 857 cancer-free women with biopsy-confirmed benign breast disease within the Nurses' Health Study (NHS) and NHSII cohorts. Percentage of each tissue was measured on whole slide images using a deep-learning algorithm and then log-transformed. Alcohol consumption (recent and cumulative average) was assessed with semi-quantitative food frequency questionnaires. Regression estimates were adjusted for known breast cancer risk factors. All tests were 2-sided. RESULTS: Alcohol was inversely associated with % of stroma and fibroglandular tissue (recent ≥ 22 g/day vs. none: stroma: ß = - 0.08, 95% Confidence Interval [CI] - 0.13; - 0.03; fibroglandular: ß = - 0.08, 95% CI - 0.13; - 0.04; cumulative ≥ 22 g/day vs. none: stroma: ß = - 0.08, 95% CI - 0.13; - 0.02; fibroglandular: ß = - 0.09, 95% CI - 0.14; - 0.04) and positively associated with fat % (recent ≥ 22 g/day vs. none: ß = 0.30, 95% CI 0.03; 0.57; cumulative ≥ 22 g/day vs. none: ß = 0.32, 95% CI 0.04; 0.61). In stratified analysis, alcohol consumption was not associated with tissue measures in premenopausal women. In postmenopausal women, cumulative alcohol use was inversely associated with % of stroma and fibroglandular tissue and positively associated with fat % (≥ 22 g/day vs. none: stroma: ß = - 0.16, 95% CI - 0.28; - 0.07; fibroglandular: ß = - 0.18, 95% CI - 0.28; - 0.07; fat: ß = 0.61, 95% CI 0.01; 1.22), with similar results for recent alcohol use. CONCLUSION: Our findings suggest that alcohol consumption is associated with smaller % of stroma and fibroglandular tissue and a greater % of fat in postmenopausal women. Future studies are warranted to confirm our findings and to elucidate the underlying biological mechanisms.

Associations of stem cell markers in benign breast tissue with subsequent breast cancer risk.

We examined associations of stem cell markers CD44, CD24, and ALDH1A1 in benign breast biopsy samples with subsequent breast cancer (BCa) risk and explored if these associations were mediated by mammographic breast density (MBD). We included 101 BCa cases/375 controls, all with previous biopsy-confirmed benign breast disease (BBD) within the Nurses' Health Study (NHS) and NHSII. The data on BCa risk factors were obtained from biennial questionnaires. MBD was assessed with computer-assisted techniques. Immunohistochemistry (IHC) was done on BBD tissue microarrays. For each core, the IHC expression was assessed using a semi-automated method, and expressed as % of cells that stained positive for a specific marker out of the total cell count. Logistic regression was used to examine the associations of each marker's expression of each (in epithelium and stroma) with BCa risk, adjusted for risk factors. Stromal CD44 expression was inversely associated with BCa risk (OR for ≥10% vs. <10%=0.58, 95% CI 0.34, 1.00). Combined stromal + epithelial CD24 expression was inversely associated with BCa risk (>50% vs. 0-10% OR=0.17, 95% CI 0.04-0.81, p-trend =0.03). Stromal CD24 and ALDH1A1 as well as epithelial expression of any of the three markers were not associated with BCa risk. In a smaller subset of women with available MBD, these observed associations did not appear to be mediated by MBD. Our findings suggest inverse associations of CD44 in stroma and combined stromal + epithelial CD24 with BCa risk. Future studies are warranted to confirm our findings and to examine these associations by BBD subtype.

Association of body mass index and inflammatory dietary pattern with breast cancer pathologic and genomic immunophenotype in the nurses' health study.

BACKGROUND: Breast tumor immune infiltration is clearly associated with improved treatment response and outcomes in breast cancer. However, modifiable patient factors associated with breast cancer immune infiltrates are poorly understood. The Nurses' Health Study (NHS) offers a unique cohort to study immune gene expression in tumor and adjacent normal breast tissue, immune cell-specific immunohistochemistry (IHC), and patient exposures. We evaluated the association of body mass index (BMI) change since age 18, physical activity, and the empirical dietary inflammatory pattern (EDIP) score, all implicated in systemic inflammation, with immune cell-specific expression scores. METHODS: This population-based, prospective observational study evaluated 882 NHS and NHSII participants diagnosed with invasive breast cancer with detailed exposure and gene expression data. Of these, 262 women (training cohort) had breast tumor IHC for four classic immune cell markers (CD8, CD4, CD20, and CD163). Four immune cell-specific scores were derived via lasso regression using 105 published immune expression signatures' association with IHC. In the remaining 620 patient evaluation cohort, we evaluated association of each immune cell-specific score as outcomes, with BMI change since age 18, physical activity, and EDIP score as predictors, using multivariable-adjusted linear regression. RESULTS: Among women with paired expression/IHC data from breast tumor tissue, we identified robust correlation between novel immune cell-specific expression scores and IHC. BMI change since age 18 was positively associated with CD4+ (ß = 0.16; p = 0.009), and CD163 novel immune scores (ß = 0.14; p = 0.04) in multivariable analyses. In other words, for each 10 unit (kg/m2) increase in BMI, the percentage of cells positive for CD4 and CD163 increased 1.6% and 1.4%, respectively. Neither physical activity nor EDIP was significantly associated with any immune cell-specific expression score in multivariable analyses. CONCLUSIONS: BMI change since age 18 was positively associated with novel CD4+ and CD163+ cell scores in breast cancer, supporting further study of the effect of modifiable factors like weight gain on the immune microenvironment.

Immunohistochemistry scoring of breast tumor tissue microarrays: A comparison study across three software applications.

Digital pathology can efficiently assess immunohistochemistry (IHC) data on tissue microarrays (TMAs). Yet, it remains important to evaluate the comparability of the data acquired by different software applications and validate it against pathologist manual interpretation. In this study, we compared the IHC quantification of 5 clinical breast cancer biomarkers-estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), and cytokeratin 5/6 (CK5/6)-across 3 software applications (Definiens Tissue Studio, inForm, and QuPath) and benchmarked the results to pathologist manual scores. IHC expression for each marker was evaluated across 4 TMAs consisting of 935 breast tumor tissue cores from 367 women within the Nurses' Health Studies; each women contributing three 0.6-mm cores. The correlation and agreement between manual and software-derived results were primarily assessed using Spearman's ρ, percentage agreement, and area under the curve (AUC). At the TMA core-level, the correlations between manual and software-derived scores were the highest for HER2 (ρ ranging from 0.75 to 0.79), followed by ER (0.69-0.71), PR (0.67-0.72), CK5/6 (0.43-0.47), and EGFR (0.38-0.45). At the case-level, there were good correlations between manual and software-derived scores for all 5 markers (ρ ranging from 0.43 to 0.82), where QuPath had the highest correlations. Software-derived scores were highly comparable to each other (ρ ranging from 0.80 to 0.99). The average percentage agreements between manual and software-derived scores were excellent for ER (90.8%-94.5%) and PR (78.2%-85.2%), moderate for HER2 (65.4%-77.0%), highly variable for EGFR (48.2%-82.8%), and poor for CK5/6 (22.4%-45.0%). All AUCs across markers and software applications were ≥0.83. The 3 software applications were highly comparable to each other and to manual scores in quantifying these 5 markers. QuPath consistently produced the best performance, indicating this open-source software is an excellent alternative for future use.

The Multidimensional Impacts of Inequities for Tangata Whaikaha Maori (Indigenous Maori with Lived Experience of Disability) in Aotearoa, New Zealand.

People with lived experience of disability have poorer health and socioeconomic outcomes than people without it. However, within this population, certain social groups are more likely to experience poorer outcomes due to the impacts of multiple intersecting forms of oppression including colonisation, coloniality and racism. This paper describes the multidimensional impacts of inequities for Indigenous tangata whaikaha Maori (Maori with lived experience of disability). Semi-structured in-depth interviews were conducted with 28 tangata whaikaha Maori and their whanau (extended family) using a kaupapa Maori Research methodology. An equity framework was used to analyse the data. The results describe: (1) inequitable access to the determinants of health and well-being; (2) inequitable access to and through health and disability care; (3) differential quality of health and disability care received; and (4) Indigenous Maori-driven solutions. These data confirm that tangata whaikaha Maori in the nation-state known as New Zealand experience racism, ableism and disablism, compounded by the intersection between these types of discrimination. Recommendations from the data support the inclusion of tangata whaikaha Maori in decision-making structures, including all policies and practices, along with equal partnership rights when it comes to designing health and disability systems and services.

Systemic Medications Associated With Hair Texture Changes.

BACKGROUND: In addition to hair loss, alterations in hair texture can be a worrisome side effect of certain medications yet are seldom reported and poorly characterized. OBJECTIVE: To systematically analyze the scientific literature to characterize medication-associated hair texture changes. METHODS: Relevant primary literature within PubMed and Cochrane was reviewed from 1985-2021 including 31 articles (1 randomized controlled trial with texture changes incidentally noted, 6 cohort, 1 cross-sectional, 23 case studies), comprising 2594 patients. RESULTS: Texture changes were associated primarily with antineoplastic agents (n = 97), antiepileptics (n = 56), retinoids (n = 15), immunomodulators (n = 3), and antiretroviral therapy (n = 1). Average age was 48.4 years old (41.2% female). De novo or exaggerated curling patterns were most commonly reported. Average time to texture change varied from 4.5 months (immunomodulators) to 17 months (antiretrovirals). Prognosis was seldom discussed with reversibility noted across all medication classes (n = 17/21; 3 weeks to 5 years post therapy). Irreversible changes were linked with antiretrovirals, retinoids, and antineoplastics. LIMITATIONS: Inability to define true incidence rates, ethnicity, and severity of texture changes due to the nature of available literature. CONCLUSIONS: Hair texture changes are potential side effects of antineoplastics, antiepileptics, retinoids, immunomodulators, and antiretroviral therapy. As these can have associated psychosocial impact, awareness among prescribing physicians is important.J Drugs Dermatol. 2022;21(9):989-996 doi:10.36849/JDD.6852.

Loss of PTEN Expression, PIK3CA Mutations, and Breast Cancer Survival in the Nurses' Health Studies.

BACKGROUND: The relationships between PTEN loss and/or PIK3CA mutation and breast cancer prognosis remain controversial. We aim to examine the associations in large epidemiologic cohorts. METHODS: We followed women with invasive breast cancer from the Nurses' Health Studies with available data on tumor PTEN expression (n = 4,111) and PIK3CA mutation (n = 2,930). PTEN expression was evaluated by IHC and digitally scored (0%-100%). Pyrosequencing of six hotspot mutations of PIK3CA was performed. RESULTS: We found loss of PTEN expression (≤10%) occurred in 17% of cases, and PIK3CA mutations were detected in 11% of cases. After adjusting for clinical and lifestyle factors, PTEN loss was not associated with worse breast cancer-specific mortality among all samples [HR, 0.85; 95% confidence intervals (CI), 0.71-1.03] or among estrogen receptor (ER)-positive tumors (HR, 0.99; 95% CI, 0.79-1.24). However, among ER-negative tumors, PTEN loss was associated with lower breast cancer-specific mortality (HR, 0.68; 95% CI, 0.48-0.95). PIK3CA mutation was not strongly associated with breast cancer-specific mortality (HR, 0.89; 95% CI, 0.67-1.17). Compared with tumors without PTEN loss and without PIK3CA mutation, those with alterations (n = 540) were not at higher risk (HR, 1.07; 95% CI, 0.86-1.34). However, women with both PTEN loss and PIK3CA mutation (n = 38) were at an increased risk of breast cancer-specific mortality (HR, 1.65; 95% CI, 0.83-3.26). CONCLUSIONS: In this large epidemiologic study, the PTEN-mortality association was more pronounced for ER-negative tumors, and the joint PTEN loss and PIK3CA mutation may be associated with worse prognosis. IMPACT: Further studies with a larger sample of ER-negative tumors are needed to replicate our findings and elucidate underlying mechanisms.

Invasive lobular carcinoma with extracellular mucin (ILCEM): clinicopathologic and molecular characterization of a rare entity.

Invasive lobular carcinoma with extracellular mucin (ILCEM) is a rare histologic subtype of breast cancer. Little is known about the pathologic or genomic signatures that distinguish ILCEM from classic invasive lobular carcinoma (ILC) or mucinous carcinoma. We studied 17 breast cancers with lobular morphology and extracellular mucin. Thirteen tumors with sufficient tissue for DNA extraction were analyzed by a next generation sequencing (NGS) assay that interrogates 447 genes for mutations and copy number variations (CNVs). Median patient age was 66 yrs (range: 31-77 yrs). Sixteen patients presented with masses, 7 of which were >2 cm. Seven patients had lymph node metastases. The cases of ILCEM were moderately (n = 13) or poorly differentiated (n = 4), frequently exhibiting variant morphology that has not been previously described or emphasized, including grade 3 nuclei (n = 11), diffuse signet ring cells (n = 10), solid growth (n = 4), tumor necrosis (n = 3) or apocrine features (n = 2). All tumors showed absent or reduced membranous E-cadherin expression. Concurrent lobular carcinoma in situ (LCIS) was seen in 11/17 cases, 1 of which was a striking example of signet ring cell LCIS with extracellular mucin. Receptor profiles were ER+/HER2- (n = 15) and ER+/HER2+ (n = 2). With a median follow-up of 83.5 months (range: 3-171 months) in 12 patients with available information, 8 patients had recurrences resulting in 4 cancer-related deaths. The most common CNVs were 16q loss (n = 11) and 1q gain (n = 9). CDH1 gene-level alterations were detected in all but one case, including frameshift (n = 7), nonsense (n = 2), and donor splice site (n = 1) mutations and indels (n = 2). Recurrent mutations were also seen in PIK3CA (n = 3), POLQ (n = 3), TP53 (n = 3), ERBB3 (n = 3), ERBB2 (n = 2), and RUNX1 (n = 2). Genes with recurrent amplifications included GATA3 (n = 4), FOXA1 (n = 3), CCND1 (n = 2). Our data highlights ILCEM as a distinct variant of ILC that often presents with higher-grade and variant morphologic features and is associated with an aggressive clinical course. NGS data support an overall lobular-type molecular profile and reveal potentially targetable alterations in a subset of cases with recurrence.

Upgrade Rates of Pure, Radiology-Pathology Concordant Lobular Neoplasia Diagnosed on Breast Core Needle Biopsy: Is Surgical Excision Warranted?

OBJECTIVE: To determine upgrade rates of lobular neoplasia (LN) to malignancy and evaluate factors that may predict upgrade. METHODS: From 5/1/2003 to 12/30/2015, breast lesions diagnosed as LN (atypical lobular hyperplasia [ALH] or classic lobular carcinoma in-situ [LCIS]) on core biopsy that underwent surgical excision or at least 2 years imaging follow-up were identified. A subspecialty trained breast radiologist and pathologist reviewed imaging and pathology slides to confirm diagnosis and to determine if LN represented the target lesion, part of the target lesion, or an incidental finding. Imaging features, original BI-RADS final assessment category, biopsy method, biopsy device and final pathologic diagnosis were documented. Cases with both ALH and LCIS were classified as LCIS for analysis. Reason for biopsy of BI-RADS 2-3 was patient or referring physician preference. Upgrade rates to malignancy were determined for all cases. RESULTS: In this study 73.7% (115/156) lesions were ALH and 26.3% (41/156) were LCIS+/-ALH. Surgical excision and imaging follow-up were performed in 71.2% (111/156) and 28.8% (45/156), respectively. Upgrade rates for ALH and LCIS were 0.0% (0/115) and 7.3% (3/41), respectively. Cancer developed at a site separate from core biopsy in 1.7% (2/115) ALH and 7.3% (3/41) LCIS cases. We found no association of upgrade rate with biopsy type, BI-RADS or target/part of target lesion versus incidental. CONCLUSION: Our study supports consideration of excision for LCIS, given 7.3% upgrade rate. Conversely, imaging surveillance might be appropriate following diagnosis of ALH alone.

Reliability of CD44, CD24, and ALDH1A1 immunohistochemical staining: Pathologist assessment compared to quantitative image analysis.

Background: The data on the expression of stem cell markers CD44, CD24, and ALDH1A1 in the breast tissue of cancer-free women is very limited and no previous studies have explored the agreement between pathologist and computational assessments of these markers. We compared the immunohistochemical (IHC) expression assessment for CD44, CD24, and ALDH1A1 by an expert pathologist with the automated image analysis results and assessed the homogeneity of the markers across multiple cores pertaining to each woman. Methods: We included 81 cancer-free women (399 cores) with biopsy-confirmed benign breast disease in the Nurses' Health Study (NHS) and NHSII cohorts. IHC was conducted with commercial antibodies [CD44 (Dako, Santa Clara, CA, USA) 1:25 dilution; CD24 (Invitrogen, Waltham, MA, USA) 1:200 dilution and ALDH1A1 (Abcam, Cambridge, United Kingdom) 1:300 dilution]. For each core, the percent positivity was quantified by the pathologist and Definiens Tissue Studio. Correlations between pathologist and computational scores were evaluated with Spearman correlation (for categorical positivity: 0, >0-<1, 1-10, >10-50, and >50%) and sensitivity/specificity (for binary positivity defined with 1 and 10% cut-offs), using the pathologist scores as the gold standard. Expression homogeneity was examined with intra-class correlation (ICC). Analyses were stratified by core [normal terminal duct-lobular units (TDLUs), benign lesions] and tissue type (epithelium, stroma). Results: Spearman correlation between pathologist and Definiens ranged between 0.40-0.64 for stroma and 0.66-0.68 for epithelium in normal TDLUs cores and between 0.24-0.60 for stroma and 0.61-0.64 for epithelium in benign lesions. For stroma, sensitivity and specificity ranged between 0.92-0.95 and 0.24-0.60, respectively, with 1% cut-off and between 0.43-0.88 and 0.73-0.85, respectively, with 10% cut-off. For epithelium, 10% cut-off resulted in better estimates for both sensitivity and specificity. ICC between the cores was strongest for CD44 for both stroma and epithelium in normal TDLUs cores and benign lesions (range 0.74-0.80). ICC for CD24 and ALDH1A ranged between 0.42-0.63 and 0.44-0.55, respectively. Conclusion: Our findings show that computational assessments for CD44, CD24, and ALDH1A1 exhibit variable correlations with manual assessment. These findings support the use of computational platforms for IHC evaluation of stem cell markers in large-scale epidemiologic studies. Pilot studies maybe also needed to determine appropriate cut-offs for defining staining positivity.