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Breast cancer risk factors and circulating anti-Müllerian hormone concentration in healthy premenopausal women

Clendenen, Tess V; Ge, Wenzhen; Koenig, Karen L; Afanasyeva, Yelena; Agnoli, Claudia; Bertone-Johnson, Elizabeth; Brinton, Louise A; Darvishian, Farbod; Dorgan, Joanne F; Eliassen, A Heather; Falk, Roni T; Hallmans, Göran; Hankinson, Susan E; Hoffman-Bolton, Judith; Key, Timothy J; Krogh, Vittorio; Nichols, Hazel B; Sandler, Dale P; Schoemaker, Minouk J; Sluss, Patrick M; Sund, Malin; Swerdlow, Anthony J; Visvanathan, Kala; Liu, Mengling; Zeleniuch-Jacquotte, Anne
CONTEXT/BACKGROUND:In a previous study we reported that anti-Müllerian hormone (AMH), a marker of ovarian reserve, is positively associated with breast cancer risk, consistent with other studies. OBJECTIVE:Assess whether risk factors for breast cancer are correlates of AMH concentration. DESIGN/METHODS:Cross-sectional. PARTICIPANTS/METHODS:3831 healthy premenopausal women (aged 21-57, 87% aged 35-49). SETTING/METHODS:Ten cohort studies, general population. RESULTS:Adjusting for age and cohort, we observed positive associations of AMH with age at menarche (p<0.0001) and parity (p=0.0008), and an inverse association with hysterectomy/partial oophorectomy (p=0.0008). Compared to women of normal weight (BMI 18.5-24.9 kg/m 2, AMH was lower (relative geometric mean difference 27%, p<0.0001) among women who were obese (BMI>30). Current oral contraceptive use and current/former smoking were associated with lower AMH concentration than never use (40% and 12% lower, respectively, p<0.0001). We observed higher AMH concentrations among women who had had a benign breast biopsy (15% higher, p=0.03), a surrogate for benign breast disease, an association that has not been reported. In analyses stratified by age (<40/≥40), associations of AMH with BMI and oral contraceptives were similar in younger and older women, while associations with the other factors (menarche, parity, hysterectomy/partial oophorectomy, smoking, and benign breast biopsy) were limited to women ≥40 (p-interaction<0.05). CONCLUSION/CONCLUSIONS:This is the largest study of AMH and breast cancer risk factors among women from the general population (not presenting with infertility), and suggests that most of the associations are limited to women over 40, who are approaching menopause and whose AMH concentration is declining.
PMID: 34157104
ISSN: 1945-7197
CID: 4918342

Genetic profile of primary mucinous cystadenocarcinoma of the breast-A case report [Case Report]

Lin, Lawrence Hsu; Hernandez, Osvaldo; Zhu, Kelsey; Guth, Amber; Cotzia, Paolo; Darvishian, Farbod
Primary mucinous cystadenocarcinoma of the breast is a rare neoplasm with few reports in the literature. Here, we report for the first time a comprehensive genetic profile of a primary mucinous cystadenocarcinoma of the breast, using next-generation sequencing 580 cancer-associated gene panel. Mutations in TP53, RB1, and BAP1 were identified. The findings suggest that this tumor is driven mostly by abnormalities in tumor suppressor genes, primarily involved in cell cycle control and chromatin remodeling. Molecular characterization of additional primary mucinous cystadenocarcinomas of the breast is warranted and might provide information related to its biology and behavior.
PMID: 34180564
ISSN: 1524-4741
CID: 4926202

Molecular Analysis of Encapsulated Papillary Carcinoma of the Breast with and without Invasion

Schwartz, Christopher J; Boroujeni, Amir Momeni; Khodadai-Jamayran, Alireza; Heguy, Adriana; Snuderl, Matija; Jour, George; Cotzia, Paolo; Darvishian, Farbod
Encapsulated papillary carcinomas (EPC) of the breast is a unique variant of papillary carcinoma confined to a cystic space with absent or attenuated myoepithelial cell layer. Although staged as an in-situ lesion, it can be associated with invasive ductal carcinoma (IDC). We sought to compare the genomic characteristics of pure EPC and EPC with associated invasive carcinoma (EPCi) at the genomic level. All cases of EPCi harbored recurrent hotspot mutations in PIK3CA. PIK3CA, KMT2A and CREBBP deleterious somatic events were found across both tumor groups, irrespective of invasion status. At the whole transcriptomic level, EPCi cases displayed remarkably similar mRNA profiles when compared to EPC. When EPCi cases were compared with their corresponding IDC, despite significant overlap, we identified differential gene expression in 39 genes with enrichment of multiple pathways including extracellular matrix regulation, cell adhesion and collagen fibril organization. Despite morphologic, genotypic and transcriptomic overlap between pure EPC and EPCi, the latter tumors are likely advanced lesions with PIK3CA activating mutations and enrichment of stromal-related genes implicated in the switch to IDC.
PMID: 33667422
ISSN: 1532-8392
CID: 4801982

Optimization of an automated tumor-infiltrating lymphocyte algorithm for improved prognostication in primary melanoma

Chou, Margaret; Illa-Bochaca, Irineu; Minxi, Ben; Darvishian, Farbod; Johannet, Paul; Moran, Una; Shapiro, Richard L; Berman, Russell S; Osman, Iman; Jour, George; Zhong, Hua
Tumor-infiltrating lymphocytes (TIL) have potential prognostic value in melanoma and have been considered for inclusion in the American Joint Committee on Cancer (AJCC) staging criteria. However, interobserver discordance continues to prevent the adoption of TIL into clinical practice. Computational image analysis offers a solution to this obstacle, representing a methodological approach for reproducibly counting TIL. We sought to evaluate the ability of a TIL-quantifying machine learning algorithm to predict survival in primary melanoma. Digitized hematoxylin and eosin (H&E) slides from prospectively enrolled patients in the NYU melanoma database were scored for % TIL using machine learning and manually graded by pathologists using Clark's model. We evaluated the association of % TIL with recurrence-free survival (RFS) and overall survival (OS) using Cox proportional hazards modeling and concordance indices. Discordance between algorithmic and manual TIL quantification was assessed with McNemar's test and visually by an attending dermatopathologist. In total, 453 primary melanoma patients were scored using machine learning. Automated % TIL scoring significantly differentiated survival using an estimated cutoff of 16.6% TIL (log-rank P < 0.001 for RFS; P = 0.002 for OS). % TIL was associated with significantly longer RFS (adjusted HR = 0.92 [0.84-1.00] per 10% increase in % TIL) and OS (adjusted HR = 0.90 [0.83-0.99] per 10% increase in % TIL). In comparison, a subset of the cohort (n = 240) was graded for TIL by melanoma pathologists. However, TIL did not associate with RFS between groups (P > 0.05) when categorized as brisk, nonbrisk, or absent. A standardized and automated % TIL scoring algorithm can improve the prognostic impact of TIL. Incorporation of quantitative TIL scoring into the AJCC staging criteria should be considered.
PMID: 33005020
ISSN: 1530-0285
CID: 4617292

Upgrade Rate of Intraductal Papilloma Diagnosed on Core Needle Biopsy in a Single Institution

Lin, Lawrence Hsu; Ozerdem, Ugur; Cotzia, Paolo; Lee, Jiyon; Chun, Jennifer; Schnabel, Freya; Darvishian, Farbod
The management of intraductal papilloma (IDP) diagnosed on core needle biopsy (CNB) is controversial due to the variable upgrade rates to breast carcinoma (BC) on subsequent surgical excision reported in the literature. The purpose of our study was to investigate the upgrade rate of IDP diagnosed on CNB to BC in subsequent surgical excision and the impact of clinical, pathologic and radiologic variables. This is a retrospective cohort of all women who had a diagnosis of IDP on a CNB between 2005 and 2018 in a tertiary academic center with subsequent surgical excision. Upgrade was defined as ductal carcinoma in situ (DCIS) and invasive carcinoma on surgical excision. Statistical analyses included Pearson's chi-square, Wilcoxon rank-sum and logistic regression. A total of 216 women with IDP in a CNB were included. Nineteen patients (8.8%) upgraded to BC in the overall cohort, including 14 DCIS and 5 invasive carcinomas. An upgrade rate of 27% was found in atypical IDP (14 of 51 cases), while only 3% of pure IDP upgraded to BC (5 of 165 cases). Older age (>53 years) at time of biopsy (OR=1.05, 95%CI 1.01-1.09, p=0.027) and concomitant atypical ductal hyperplasia (ADH) (OR=9.69, 95%CI 3.37-27.81, p<0.0001) were significantly associated with upgrade. Our results support surgical excision of IDP on CNB when associated with ADH or diagnosed in women older than 53 years of age. The low surgical upgrade rate of 3% for pure IDP on CNB in younger women should be part of the management discussion.
PMID: 33159966
ISSN: 1532-8392
CID: 4662082

Concurrent Identification of Novel EGFR-SEPT14 Fusion and ETV6-RET Fusion in Secretory Carcinoma of the Salivary Gland

Black, Margaret; Liu, Cheng Z; Onozato, Maristela; Iafrate, Anthony John; Darvishian, Farbod; Jour, George; Cotzia, Paolo
Salivary gland secretory carcinoma, also termed mammary analogue secretory carcinoma (MASC), is a recently described salivary gland neoplasm with characteristic histomorphologic findings similar to those of secretory carcinoma of the breast and harboring recurrent ETV6-NTRK3 fusions. Recent findings have expanded the molecular profile of salivary gland secretory carcinoma to include multiple novel ETV6 fusion partners, including RET, MET, and MAML3. Here, we report a case of cystic MASC with cribriform and papillary histology harboring two gene fusions, ETV6-RET and EGFR-SEPT14, identified by targeted RNA sequencing. The presence of the rearrangements was confirmed by FISH, RT-PCR, and Sanger sequencing. This is the first EGFR-SEPT14 fusion reported in secretory carcinoma as a single event or in association with an ETV6 rearrangement. This finding adds to the expanding molecular profile of this tumor entity, and may translate into novel treatment strategies.
PMID: 31502214
ISSN: 1936-0568
CID: 4087752

TERT, BRAF, and NRAS mutational heterogeneity between paired primary and metastatic melanoma tumors

Chang, Gregory A; Wiggins, Jennifer M; Corless, Broderick C; Syeda, Mahrukh M; Tadepalli, Jyothirmayee S; Blake, Shria; Fleming, Nathaniel; Darvishian, Farbod; Pavlick, Anna; Berman, Russell; Shapiro, Richard; Shao, Yongzhao; Karlin-Neumann, George; Spittle, Cindy; Osman, Iman; Polsky, David
Mutational heterogeneity can contribute to therapeutic resistance in solid cancers. In melanoma, the frequency of inter- and intra-tumoral heterogeneity is controversial. We examined mutational heterogeneity within individual melanoma patients using multi-platform analysis of commonly mutated driver and non-passenger genes. We analyzed paired primary and metastatic tumors from 60 patients, and multiple metastatic tumors from 39 patients whose primary tumors were unavailable (n=271 tumors). We used a combination of multiplex SNaPshot assays, Sanger Sequencing, Mutation-specific PCR, or droplet digital PCR to determine the presence of BRAFV600, NRASQ61, and TERT-124C>T and TERT-146C>T mutations. Mutations were detected in BRAF (39%), NRAS (21%) and/or TERT (78%). Thirteen patients had TERTmutant discordant tumors; seven of these had a single tumor with both TERT-124C>T and TERT-146C>T mutations present at different allele frequencies. Two patients had both BRAF and NRAS mutations; one in different tumors and the other had a single tumor with both mutations. One patient with a BRAFmutant primary lacked mutant BRAF in least one of their metastases. Overall, we identified mutational heterogeneity in 18/99 (18%) patients. These results suggest that some primary melanomas may be comprised of subclones with differing mutational profiles. Such heterogeneity may be relevant to treatment responses and survival outcomes.
PMID: 32087194
ISSN: 1523-1747
CID: 4313462

Pathologic Evaluation of Breast Tissue From Transmasculine Individuals Undergoing Gender-Affirming Chest Masculinization

Hernandez, Andrea; Schwartz, Christopher J; Warfield, Dana; Thomas, Kristen M; Bluebond-Langner, Rachel; Ozerdem, Ugur; Darvishian, Farbod
CONTEXT.—/UNASSIGNED:Bilateral mastectomy for chest masculinization is one of the gender-affirming procedures for transmasculine individuals. OBJECTIVE.—/UNASSIGNED:To optimize gross handling protocols and assess histopathologic findings in transmasculine breast tissue specimens. DESIGN.—/UNASSIGNED:We identified all gender-affirming mastectomies from 2015 to 2018. We sequentially identified reduction mammoplasty (RM) cases for macromastia from the same period as control. Significant findings were defined as atypical ductal or lobular hyperplasia (ADH, ALH), ductal or lobular carcinoma in situ (DCIS, LCIS), or invasive carcinoma. RESULTS.—/UNASSIGNED:Significant findings were present in 6 of 211 gender-affirming mastectomies (2.8%) as follows: ADH (n = 5) and LCIS together with ALH (n = 1). By comparison, 19 of 273 RM specimens (7%) yielded significant findings as follows: ALH (n = 11), ADH (n = 4), LCIS (n = 2), DCIS (n = 1), and invasive lobular carcinoma (n = 1). In the gender-affirming group, 142 transmen underwent androgen therapy before surgery, of whom 2 had significant pathologic findings. Thirty and 41 individuals had a family history of breast cancer in the gender-affirming and RM group, of whom 1 and 3 individuals had significant pathologic findings, respectively. CONCLUSIONS.—/UNASSIGNED:Our study demonstrates that we handle transmasculine mastectomy specimens by examining 2.8 times more slides on average than for RMs, with a 2.5 times lower rate of significant pathologic findings. Prior family history of breast cancer or the use of androgen therapy before surgery in gender-affirming individuals did not increase the risk of identifying significant breast lesions. We recommend submitting 4 tissue blocks per mastectomy for individuals undergoing gender-affirming breast surgery.
PMID: 31816268
ISSN: 1543-2165
CID: 4234122

Sentinel lymph node positivity in patients undergoing mastectomies for ductal carcinoma in situ (DCIS)

Price, Alison; Schnabel, Freya; Chun, Jennifer; Kaplowitz, Elianna; Goodgal, Jenny; Guth, Amber; Axelrod, Deborah; Shapiro, Richard; Mema, Eralda; Moy, Linda; Darvishian, Farbod; Roses, Daniel
Current guidelines recommend sentinel lymph node biopsy (SLNB) for patients undergoing mastectomy for a preoperative diagnosis of ductal carcinoma in situ (DCIS). We examined the factors associated with sentinel lymph node positivity for patients undergoing mastectomy for a diagnosis of DCIS on preoperative core biopsy (PCB). The Institutional Breast Cancer Database was queried for patients with PCB demonstrating pure DCIS followed by mastectomy and SLNB from 2010 to 2018. Patients were divided according to final pathology (DCIS or invasive cancer). Clinico-pathologic variables were analyzed using Pearson's chi-squared, Wilcoxon Rank-Sum and logistic regression. Of 3145 patients, 168(5%) had pure DCIS on PCB and underwent mastectomy with SLNB. On final mastectomy pathology, 120(71%) patients had DCIS with 0 positive sentinel lymph nodes (PSLNs) and 48(29%) patients had invasive carcinoma with 5(10%) cases of ≥1 PSLNs. Factors positively associated with upstaging to invasive cancer in univariate analysis included age (P = .0289), palpability (P < .0001), extent of disease on imaging (P = .0121), mass on preoperative imaging (P = .0003), multifocality (P = .0231) and multicentricity (P = .0395). In multivariate analysis, palpability (P = .0080), extent of disease on imaging (P = .0074) and mass on preoperative imaging (P = .0245) remained significant (Table 2). In a subset of patients undergoing mastectomy for DCIS with limited disease on preoperative evaluation, SLNB may be omitted as the risk of upstaging is low. However, patients who present with clinical findings of palpability, large extent of disease on imaging and mass on preoperative imaging have a meaningful risk of upstaging to invasive cancer, and SLNB remains important for management.
PMID: 31957944
ISSN: 1524-4741
CID: 4272692

Functional analysis of RPS27 mutations and expression in melanoma

Floristán, Alfredo; Morales, Leah; Hanniford, Douglas; Martinez, Carlos; Castellano-Sanz, Elena; Dolgalev, Igor; Ulloa-Morales, Alejandro; Vega-Saenz de Miera, Eleazar; Moran, Una; Darvishian, Farbod; Osman, Iman; Kirchhoff, Tomas; Hernando, Eva
Next-generation sequencing has enabled genetic and genomic characterization of melanoma to an unprecedent depth. However, the high mutational background plus the limited deep-coverage whole-genome sequencing performed on cutaneous melanoma samples, make difficult the identification of novel driver mutations. We sought to explore the somatic mutation portfolio in exonic and gene regulatory regions in human melanoma samples, for which we performed targeted sequencing of tumors and matched germline DNA samples from 89 melanoma patients, identifying known and novel recurrent mutations. Two recurrent mutations found in the RPS27 promoter associated with decreased RPS27 mRNA levels in vitro. Data mining and IHC analyses revealed a bimodal pattern of RPS27 expression in melanoma, with RPS27-low patients displaying worse prognosis. In vitro characterization of RPS27-high and -low melanoma cell lines, as well as loss-of-function experiments, demonstrated that high RPS27 status provides increased proliferative and invasive capacities, while low RPS27 confers survival advantage in low-attachment and resistance to therapy. Additionally, we demonstrate that 10 other cancer types harbor bimodal RPS27 expression and in those, similarly to melanoma, RPS27-low expression associates with worse clinical outcomes. RPS27 promoter mutation could thus represent a mechanism of gene expression modulation in melanoma patients, which may have prognostic and predictive implications.
PMID: 31663663
ISSN: 1755-148x
CID: 4162282