Patient-Derived Triple-Negative Breast Cancer Organoids Provide Robust Model Systems That Recapitulate Tumor Intrinsic Characteristics.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with poor patient outcomes, highlighting the unmet clinical need for targeted therapies and better model systems. Here, we developed and comprehensively characterized a diverse biobank of normal and breast cancer patient-derived organoids (PDO) with a focus on TNBCs. PDOs recapitulated patient tumor intrinsic properties and a subset of PDOs can be propagated for long-term culture (LT-TNBC). Single cell profiling of PDOs identified cell types and gene candidates affiliated with different aspects of cancer progression. The LT-TNBC organoids exhibit signatures of aggressive MYC-driven, basal-like breast cancers and are largely comprised of luminal progenitor (LP)-like cells. The TNBC LP-like cells are distinct from normal LPs and exhibit hyperactivation of NOTCH and MYC signaling. Overall, this study validates TNBC PDOs as robust models for understanding breast cancer biology and progression, paving the way for personalized medicine and tailored treatment options. SIGNIFICANCE: A comprehensive analysis of patient-derived organoids of TNBC provides insights into cellular heterogeneity and mechanisms of tumorigenesis at the single-cell level.

MaTAR25 lncRNA regulates the Tensin1 gene to impact breast cancer progression.

Misregulation of long non-coding RNA (lncRNA) genes has been linked to a wide variety of cancer types. Here we report on Mammary Tumor Associated RNA 25 (MaTAR25), a nuclear enriched and chromatin associated lncRNA that plays a role in mammary tumor cell proliferation, migration, and invasion, both in vitro and in vivo. MaTAR25 functions by interacting with purine rich element binding protein B (PURB), and associating with a major downstream target gene Tensin1 (Tns1) to regulate its expression in trans. The Tns1 protein product is a critical component of focal adhesions linking signaling between the extracellular matrix and the actin cytoskeleton. Knockout of MaTAR25 results in down-regulation of Tns1 leading to a reorganization of the actin cytoskeleton, and a reduction of focal adhesions and microvilli. We identify LINC01271 as the human ortholog of MaTAR25, and importantly, increased expression of LINC01271 is associated with poor patient prognosis and metastasis. Our findings demonstrate that LINC01271 represents a potential therapeutic target to alter breast cancer progression.

Comprehensive analysis of structural variants in breast cancer genomes using single-molecule sequencing.

Improved identification of structural variants (SVs) in cancer can lead to more targeted and effective treatment options as well as advance our basic understanding of the disease and its progression. We performed whole-genome sequencing of the SKBR3 breast cancer cell line and patient-derived tumor and normal organoids from two breast cancer patients using Illumina/10x Genomics, Pacific Biosciences (PacBio), and Oxford Nanopore Technologies (ONT) sequencing. We then inferred SVs and large-scale allele-specific copy number variants (CNVs) using an ensemble of methods. Our findings show that long-read sequencing allows for substantially more accurate and sensitive SV detection, with between 90% and 95% of variants supported by each long-read technology also supported by the other. We also report high accuracy for long reads even at relatively low coverage (25×-30×). Furthermore, we integrated SV and CNV data into a unifying karyotype-graph structure to present a more accurate representation of the mutated cancer genomes. We find hundreds of variants within known cancer-related genes detectable only through long-read sequencing. These findings highlight the need for long-read sequencing of cancer genomes for the precise analysis of their genetic instability.

Smoking and alcohol drinking effect on radiotherapy associated risk of second primary cancer and mortality among breast cancer patients.

BACKGROUND: Smoking and alcohol consumption are potential risk factors for breast cancer (BC) and may modify the risk of radiotherapy-associated second primary cancer (SPC) occurrence and total mortality. We explored the joint effect of smoking, or alcohol drinking, and radiotherapy on the risk of SPC and overall mortality among BC survivals. METHODS: We conducted a cancer registry-based study of 10,676 BC cases (stage 0-III) with data on smoking and alcohol consumption at time of diagnosis and clinical and therapeutics characteristics. Multivariable Cox proportional hazard models were used to estimate Hazard Ratios [HRs] and 95% confidence interval [CI] of total and site-specific SPC and mortality adjusting for demographic and cancer related characteristics. RESULTS: The SPC risk associated with radiotherapy was higher among ever-smokers than never-smokers (p for interaction = 0.04). Compared to never-smokers/unirradiated, the adjusted HR for ever-smokers/irradiated was 1.79 (95%CI, 1.43-2.23), and for never-smokers/irradiated was 1.31 (95%CI, 1.06-1.63). Analysis by cancer site showed that for ever-smokers/irradiated the risk for hematological, gastrointestinal, gynecological urological and lung/pulmonary cancer was significantly increased by two to five-fold. Mortality was significantly higher for ever-smokers/irradiated (HR = 1.25; 95%CI, 1.06-1.47), but was lower for never-smokers/irradiated (HR = 0.85; 95%CI, 0.73-0.99). Alcohol consumption did not alter the association between radiotherapy and SPC risk, but was associated with lower mortality risk. CONCLUSION: Patients who received radiotherapy and smoked before or at time of BC diagnosis have an increased risk for specific SPCs; drinking alcohol did not alter the effect of radiotherapy. Smoking significantly increased mortality risk reducing the protective effect of radiotherapy treatment.

Ossifying fibromyxoid tumor of the breast mimicking fibroadenoma: a case report and differential diagnoses.

An 80-year-old woman presented with a palpable mass in the right breast. Mammographic findings were consistent with calcified fibroadenoma. An ultrasound was performed that showed a solid nodule with peripheral calcification. A core biopsy was obtained that revealed a spindle cell proliferation with a shell of mature bone. The histologic features, in combination with immunohistochemical studies, were those of an ossifying fibromyxoid tumor. Complete excision of the specimen further confirmed the diagnosis. To the best of our knowledge, this is the first reported case of ossifying fibromyxoid tumor occurring in the breast. We review the current literature on ossifying fibromyxoid tumor and discuss the differential diagnoses when confronted with bland spindle cells on a core biopsy of the breast.

Classic lobular neoplasia on core biopsy: a clinical and radio-pathologic correlation study with follow-up excision biopsy.

There are no consensus guidelines for the management of lobular neoplasia diagnosed on core biopsy as the highest risk factor for cancer. This study aimed to assess the risk of upgrade (invasive carcinoma or ductal carcinoma in situ) at the site of the lobular neoplasia and any clinical, radiological or pathologic factors associated with the upgrade. We reviewed all cases with a diagnosis of lobular neoplasia on core biopsy from June 2006 to June 2011. Any cases with radio-pathologic discordance, coexistent lesion that required excision (atypical ductal hyperplasia, flat epithelial atypia, duct papilloma or radial scar) or non-classic variant of lobular carcinoma in situ (pleomorphic, mixed ductal and lobular, lobular carcinoma in situ with necrosis) were excluded from the study. Core biopsy indications included calcification in 35 (40%), non-mass like enhancement in 19 (22%), mass lesion in 31 (36%) and mass as well as calcification in two cases (2%). Follow-up excisions were studied for the presence of upgrade. The study cohort included 87 cases and showed an upgrade of 3.4% (95% confidence interval: 1-10%). Three cases showed an upgrade (one ductal carcinoma in situ and two invasive cancers). All upgraded cases were breast imaging-reporting and data system score ≥4 and associated with atypical duct hyperplasia or in situ or invasive cancer in prior or concurrent biopsies in either breast. The number of cores and lobules involved, pagetoid duct involvement, presence of microcalcification in lobular neoplasia, needle gauge and number of cores obtained showed no correlation with the upgrade. Our results suggest that with radio-pathologic concordance and no prior biopsy proven risk for breast cancer, core biopsy finding of lobular neoplasia as the highest risk lesion can be appropriately and safely managed with clinical and radiologic follow-up as an alternative to surgical excision.

Clinical outcomes of postmastectomy radiation therapy after immediate breast reconstruction.

PURPOSE: To determine the long-term complication rates and cosmetic results for patients undergoing postmastectomy radiation therapy (PMRT) after immediate reconstruction (IR). METHODS AND MATERIALS: Between January 1998 and December 2005, 92 patients underwent modified radical mastectomy, IR, and PMRT in our practice. A total of 69 patients underwent tissue expander and implant reconstruction (TE/I), and 23 underwent autologous tissue reconstruction (ATR). Follow-up regarding complications and cosmesis was obtained for all 92 patients. Complications were scored as follows: Grade 1, no discomfort; Grade 2, discomfort affecting activities of daily living; Grade 3, surgical intervention or intravenous antibiotics required; and Grade 4, removal or replacement of the reconstruction. Cosmesis was rated as either acceptable or unacceptable to the patient. Both complications and cosmesis were correlated with treatment- and patient-related factors. RESULTS: Median follow-up for all patients was 38 months. The overall rate of severe complications (Grade 3-4) was 25%. The overall rate of poor functional results (Grade 2-4) was 43.4%. When analyzed as a function of type of reconstruction, the rate of Grade 3 to 4 complications was 33.3% for TE/I vs. 0% for ATR (p = 0.001). The rate of Grade 2 to 4 complications was 55% for TE/I vs. 8.7% for ATR (p < 0.001). Acceptable cosmesis was reported in 51% of TE/I patients vs. 82.6% of ATR patients (p = 0.007). No other treatment or patient-related factors had a significant impact on either complications or cosmesis. CONCLUSION: In patients undergoing PMRT after IR, ATR is associated with fewer long-term complications and better cosmetic results than TE/I.

The mammography screening employee inreach program.

OBJECTIVE: To determine whether our health care employees were undergoing mammography screening according to American Cancer Society guidelines and to determine whether aggressive outreach, education and streamlining of mammography scheduling could improve compliance. STUDY DESIGN: All female employees at North Shore University Hospital (NSUH) and several other health system facilities (SF) were sent mailings to their homes that included breast health education and mammography screening guidelines, a questionnaire regarding their own mammography screening history and the opportunity to have their mammography screening scheduled by the Mammography Screening Employee Inreach Program (MSEIP) coordinator. RESULTS: Of the approximately 2,700 female employees aged 40 and over at NSUH and SF, 2,235 (82.7%) responded to the questionnaire, and 1,455 had a mammogram done via the MSEIP. Of the 1,455, 43% either were overdue for a mammogram or had never had one. During a second year of the MSEIP at NSUH and SF, an additional 1,706 mammograms were done. CONCLUSION: People employed in health care jobs do not necessarily avail themselves of appropriate health care screening. An aggressive program that utilized education, outreach and assistance with scheduling was effective in increasing compliance with mammography screening.