Hidden secrets of the cancer genome: unlocking the impact of non-coding mutations in gene regulatory elements.

Discoveries in the field of genomics have revealed that non-coding genomic regions are not merely "junk DNA", but rather comprise critical elements involved in gene expression. These gene regulatory elements (GREs) include enhancers, insulators, silencers, and gene promoters. Notably, new evidence shows how mutations within these regions substantially influence gene expression programs, especially in the context of cancer. Advances in high-throughput sequencing technologies have accelerated the identification of somatic and germline single nucleotide mutations in non-coding genomic regions. This review provides an overview of somatic and germline non-coding single nucleotide alterations affecting transcription factor binding sites in GREs, specifically involved in cancer biology. It also summarizes the technologies available for exploring GREs and the challenges associated with studying and characterizing non-coding single nucleotide mutations. Understanding the role of GRE alterations in cancer is essential for improving diagnostic and prognostic capabilities in the precision medicine era, leading to enhanced patient-centered clinical outcomes.

Anatomy Versus Biology: What Guides Chemotherapy Decisions in Older Patients With Breast Cancer?

INTRODUCTION: With the increasing utilization of genomic assays, such as the Oncotype DX recurrence score (RS), the relevance of anatomic staging has been questioned for select older patients with breast cancer. We sought to evaluate differences in chemotherapy receipt and/or survival among older patients based on RS and sentinel lymph node biopsy (SLNB) receipt/result. METHODS: Patients aged ≥ 65 diagnosed with pT1-2/cN0/M0 hormone-receptor-positive (HR+)/HER2-breast cancer (2010-2019) were selected from the National Cancer Database. Logistic regression was used to identify factors associated with chemotherapy receipt. Cox proportional hazards models were used to estimate the association of RS/SLNB group with overall survival. A cost-benefit study was also performed. RESULTS: Of the 75,428 patients included, the majority had an intermediate RS (58.2% versus 27.9% low, 13.8% high) and were SLNB- (85.1% versus 11.6% SLNB+, 3.3% none). Chemotherapy was recommended for 13,442 patients (17.8%). After adjustment, chemotherapy receipt was more likely with higher RS and SLNB+. After adjustment, SLNB receipt/result was only associated with overall survival among those with an intermediate RS. However, returning to the OR for SLNB is not cost-effective. CONCLUSIONS: SLNB receipt/result was associated with survival for those with an intermediate RS, but not a low or high RS, suggesting that an SLNB may indeed be unnecessary for select older patients with breast cancer.

Retained Biopsy Site Markers After Breast Lesion Surgical Resection: Associations With Residual Malignancy.

BACKGROUND. Biopsy site markers (BSMs) placed during image-guided core needle biopsy (CNB) are typically targeted for surgical excision, along with the breast imaging abnormality. Retained BSMs raise concern of incomplete resection of the breast abnormality. OBJECTIVE. The purpose of our study was to assess the frequency of residual malignancy in patients with retained BSMs identified on the initial mammography performed after breast lesion surgical excision. METHODS. This retrospective study included 30 patients (median age, 59 years) who underwent surgical resection between August 2015 and April 2022 of a borderline, high-risk, or malignant breast lesion after CNB and technically adequate preoperative image-guided localization, in whom the initial postoperative mammography report described a retained nonmigrated BSM. EMR data were extracted. The index pathology from CNB and initial surgical resection was classified as malignant or nonmalignant. The presence of residual malignancy after initial surgical resection required pathologic confirmation from subsequent tissue sampling; the absence of residual malignancy required 2 years of benign imaging follow-up. RESULTS. Thirteen specimen radiographs were interpreted intraoperatively by a surgeon with later radiologist interpretation, and 17 underwent real-time radiologist interpretation. Eighteen patients had malignant index pathology from the initially resected lesion. The frequency of residual malignancy on subsequent follow-up after initial surgical resection was higher in patients with malignant than nonmalignant index pathology (39% [7/18] vs 0% [0/12], respectively; p = .02). Among patients with malignant index pathology, the frequency of residual malignancy was higher in those without, than with, malignancy in the initial surgical specimen (80% [4/5] vs 23% [3/13]; p = .047). Also in these patients, the frequency of a positive interpretation of the initial postoperative mammography (BI-RADS category 4 or 6) was not significantly different between those with and without residual malignancy (57% [4/7] vs 55% [6/11]; p > .99). CONCLUSION. Patients with retained BSMs associated with malignant index lesions are at substantial risk of having residual malignancy. Initial postoperative mammography is not sufficient for excluding residual malignancy. CLINICAL IMPACT. Retained BSMs associated with index malignancy should be considered suspicious for residual malignancy. In this scenario, timely additional tissue sampling targeting the retained BSM is warranted, given the greater-than-2% chance of malignancy. Active surveillance is a reasonable management strategy in patients with retained BSMs from nonmalignant index lesions.

Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process. METHODS: We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens. RESULTS: We explored the clinical relevance of an insulator element located within the Chr11q22.2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR = 1.57 [1.06 - 2.33]; p = 0.023) and overall (HR = 2.65 [1.31 - 5.37], p = 0.005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC = 0.77, p < 0.01). CONCLUSION: Our study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer.

Neoadjuvant Chemotherapy and Endocrine Therapy for Older Patients with Estrogen Receptor Positive Breast Cancer: Comparison of Approaches.

BACKGROUND: Benefits of a pathologic complete response (pCR) following neoadjuvant therapy are well established, yet outcomes for older women are understudied. We sought to examine the pCR and overall survival (OS) rates of women with estrogen receptor (ER) positive breast cancer across age groups. METHODS: Women diagnosed with cT1-4, N0-3, M0, ER+/HER2- breast cancer (2010-2018) who underwent neoadjuvant chemotherapy (NACT) or neoadjuvant endocrine therapy (NET) followed by surgery were selected from the National Cancer Database and categorized by age. Differences were tested, and Cox proportional hazards models were used to estimate the association of response with OS after adjustment for covariates. RESULTS: In the 43,009-patient cohort, 84.8% received NACT and 15.2% received NET. Of those aged ≥ 70 (N = 5623), 51.0% received NACT, and 49.0% received NET. Compared with younger women receiving NACT, older women were less likely to have a breast or nodal pCR [no pCR by age: 85.1% (≥ 70 years) vs 82.2% (50-69 years) vs 77.7% (< 50 years), p < 0.001]. Rates of pCR were similarly low for all women receiving NET [no pCR by age: 95.6% (≥ 70 years) vs 95% (50-69 years) vs 96% (< 50 years), p = 0.06]. After adjustment, pCR after NACT was not associated with OS for older patients, but better survival outcomes were noted for older patients achieving pCR after NET. CONCLUSION: For women with ER+/HER2- breast cancer, pCR rates after NACT are lower in older women compared with younger women, and are equally low after NET for all women. However, pCR after NET is associated with improved OS among older women, unlike pCR after NACT.

Higher risk tumor features are not associated with higher nodal stage in patients with estrogen receptor-positive, node-positive breast cancer.

INTRODUCTION: Studies support omission of axillary lymph node dissection (ALND) for patients with sentinel node-positive disease, with ALND recommended for patients who present with clinically positive nodes. Here, we evaluate patient and tumor characteristics and pathologic nodal stage of patients with estrogen receptor-positive (ER +) breast cancer who undergo ALND to determine if differences exist based on nodal presentation. MATERIALS AND METHODS: Retrospective chart review from 2010 to 2019 defined three groups of patients with ER + breast cancer who underwent ALND for positive nodes: SLN + (positive node identified at SLN biopsy), cNUS (abnormal preoperative US and biopsy), and cNpalp (palpable adenopathy). Patients who received neoadjuvant chemotherapy or presented with axillary recurrence were excluded. RESULTS: Of 191 patients, 94 were SLN + , 40 were cNUS, and 57 were cNpalp. Patients with SLN + compared with cNpalp were younger (56 vs 64 years, p < 0.01), more often pre-menopausal (41% vs 14%, p < 0.01), and White (65% vs 39%, p = 0.01) with more tumors that were low-grade (36% vs 8%, p < 0.01). Rates of PR + (p = 0.16), levels of Ki67 expression (p = 0.07) and LVI (p = 0.06) did not differ significantly among groups. Of patients with SLN + disease, 64% had pN1 disease compared to 38% of cNUS (p = 0.1) and 40% of cNpalp (p = 0.01). On univariable analysis, tumor size (p = 0.01) and histology (p = 0.04) were significantly associated with pN1 disease, with size remaining an independent predictor on multivariable analysis (p = 0.02). CONCLUSION: Historically, higher risk features have been attributed to patients with clinically positive nodes precluding omission of ALND, but when restricting evaluation to patients with ER + breast cancer, only tumor size is associated with higher nodal stage.

SAVI SCOUT® localization of metastatic axillary lymph node prior to neoadjuvant chemotherapy for targeted axillary dissection: a pilot study.

PURPOSE: In clinically node-positive breast cancer, axillary staging after neoadjuvant chemotherapy (NAC) is optimized with targeted axillary dissection (TAD), which includes removal of the biopsy-proven metastatic lymph node (LN) in addition to sentinel lymph nodes (SLN). Localization of the clipped node is currently performed post-NAC; however, technical limitations can make detection and localization of the treated LN challenging. We prospectively evaluated the feasibility of localizing the metastatic LN with a SAVI SCOUT® reflector (SAVI) prior to NAC for targeted removal at surgery. METHODS: Twenty-five patients with stage 2/3 breast cancer underwent ultrasound-guided localization of the biopsy-proven LN with SAVI prior to NAC. After NAC, patients with clinical response underwent TAD. Primary outcome measures were rate of successful localization, days between insertion of SAVI and axillary surgery, frequency of retrieval of clipped node, and frequency of SAVI-LN as SLN. RESULTS: After NAC, 23/25 (92%) had clinical axillary down-staging and underwent TAD. Two patients with persistent palpable axillary disease underwent ALND for initial staging. Axillary surgery was performed at an average of 141 days post-SAVI insertion and the SAVI was successfully retrieved in all cases. Among 23 patients undergoing TAD, the SAVI was retrieved within a LN in all patients, whereas clip migration was observed in two patients. The median SLN removed was 4, and SAVI-LN was SLN in 22/23 patients. Axillary pCR rate was 44%. CONCLUSION: Localizing a metastatic LN with SAVI reflector prior to NAC for targeted removal at surgery is feasible and may provide technical and logistical advantages over axillary localization post-NAC. CLINICAL TRIAL REGISTRY: Clinical trials.gov identifier: NCT03411070.

Epigenetic Signatures Predict Pathologic Nodal Stage in Breast Cancer Patients with Estrogen Receptor-Positive, Clinically Node-Positive Disease.

BACKGROUND: Breast cancer patients with clinically positive nodes who undergo upfront surgery are often recommended for axillary lymph node dissection (ALND), yet more than half are found to have limited nodal disease (≤ 3 positive nodes, pN1) at surgery. In this study, we examined the efficiency of molecular classifiers in stratifying patients with clinically positive nodes to pN1 versus > pN1 disease. METHODS: We evaluated the clinical and epigenetic data of patients in The Cancer Genome Atlas with estrogen receptor-positive, human epidermal growth factor receptor 2-negative invasive ductal carcinoma who underwent ALND for node-positive disease. Patients were divided into control (pN1, ≤ 3 positive nodes) and case (> pN1, > 3 positive nodes) groups. Machine learning algorithms were trained on 50% of the cohort and validated on the remaining 50% to identify DNA methylation signatures that predict > pN1 disease. Clinical variables and epigenetic signatures were compared. RESULTS: Controls (n = 34) and case (n = 24) cohorts showed similar mean age (56.4 ± 12.2 vs. 57.6 ± 16.7 years; p = 0.77), number of nodes removed (16.1 ± 7.3 vs. 17.5 ± 6.2; p = 0.45), tumor grade (p = 0.76), presence of lymphovascular invasion (p = 0.18), extranodal extension (p = 0.17), tumor laterality (p = 0.89), and tumor location (p = 0.42). The mean number of positive nodes was significantly different (1.76 ± 0.82, pN1; 8.83 ± 5.36, > pN1; p < 0.001). Three epigenetic signatures (EpiSig14, EpiSig13, EpiSig10) based on DNA methylation patterns of the primary tumors demonstrated high accuracy in predicting > pN1 disease (area under the curve 0.98). CONCLUSIONS: Epigenetic signatures have an excellent diagnostic accuracy for stratifying nodal disease in patients with clinically positive nodes. Validation of this tool is warranted and may provide an accurate and cost-effective method of identifying patients with predicted low nodal burden who could be spared the morbidity of ALND.

Machine Learning-Based Epigenetic Classifiers for Axillary Staging of Patients with ER-Positive Early-Stage Breast Cancer.

BACKGROUND: In the era of molecular stratification and effective multimodality therapies, surgical staging of the axilla is becoming less relevant for patients with estrogen receptor (ER)-positive early-stage breast cancer (EBC). Therefore, a nonsurgical method for accurately predicting lymph node disease is the next step in the de-escalation of axillary surgery. This study sought to identify epigenetic signatures in the primary tumor that accurately predict lymph node status. PATIENTS AND METHODS: We selected a cohort of patients in The Cancer Genome Atlas (TCGA) with ER-positive, HER2-negative invasive ductal carcinomas, and clinically-negative axillae (n = 127). Clinicopathological nomograms from the Memorial Sloan Kettering Cancer Center (MSKCC) and the MD Anderson Cancer Center (MDACC) were calculated. DNA methylation (DNAm) patterns from primary tumor specimens were compared between patients with pN0 and those with > pN0. The cohort was divided into training (n = 85) and validation (n = 42) sets. Random forest was employed to obtain the combinations of DNAm features with the highest accuracy for stratifying patients with > pN0. The most efficient combinations were selected according to the area under the curve (AUC). RESULTS: Clinicopathological models displayed a modest predictive potential for identifying > pN0 disease (MSKCC AUC 0.76, MDACC AUC 0.69, p = 0.15). Differentially methylated sites (DMS) between patients with pN0 and those with > pN0 were identified (n = 1656). DMS showed a similar performance to the MSKCC model (AUC = 0.76, p = 0.83). Machine learning approaches generated five epigenetic classifiers, which showed higher discriminative potential than the clinicopathological variables tested (AUC > 0.88, p < 0.05). CONCLUSIONS: Epigenetic classifiers based on primary tumor characteristics can efficiently stratify patients with no lymph node involvement from those with axillary lymph node disease, thereby providing an accurate method of staging the axilla.

Updates on treating ductal carcinoma in situ: what's to know in 2021.

PURPOSE OF REVIEW: Ductal carcinoma in situ (DCIS) is a noninvasive stage of disease but understood to be a nonobligate precursor to invasive breast cancer. As such, women with DCIS are routinely recommended for standard breast cancer treatment to prevent progression to invasive disease. DCIS, however, represents a heterogeneous group of lesions that differs in its biologic behavior and risk of progression. Thus, optimal treatment is unclear. This review presents the clinical trials evaluating the de-escalation of therapy, attempts at risk stratification, and future directions in the management of this disease. RECENT FINDINGS: The de-escalation of therapy for patients with DCIS is being actively explored. Although no group of patients based on clinicopathologic features has yet been identified as suitable for omission of therapy, molecular tests appear better able to stratify patients at low risk for whom omission of radiation may be considered. Trials considering omission of surgery are ongoing, and the use of Herceptin and vaccine therapy are also being explored. SUMMARY: The current review provides a centralized summary enabling the clinician to better understand the complexity of DCIS and the controversies over the optimal management of this disease. It highlights the need for better risk stratification to individualize patient care. VIDEO ABSTRACT: http://links.lww.com/COOG/A77.

"Going Flat" After Mastectomy: Patient-Reported Outcomes by Online Survey.

BACKGROUND: The Going Flat movement aims to increase awareness and acceptance of mastectomy alone as a viable option for patients. Little is known about motivations and satisfaction with surgical outcomes in this population. METHODS: An online survey was administered to 931 women who had a history of uni- or bilateral mastectomy for treatment of breast cancer or elevated breast cancer risk without current breast mound reconstruction. Satisfaction with outcome and surgeon support for the patient experience were characterized using 5-level scaled scores. RESULTS: Mastectomy alone was the first choice for 73.7% of the respondents. The top two reasons for going flat were desire for a faster recovery and avoidance of a foreign body placement. Overall, the mean scaled satisfaction score was 3.72 ± 1.17 out of 5. In the multivariable analysis, low level of surgeon support for the decision to go flat was the strongest predictor of a satisfaction score lower than 3 (odds ratio [OR], 3.85; 95% confidence interval [CI], 2.59-5.72; p < 0.001). Dissatisfaction also was more likely among respondents reporting a body mass index (BMI) of 30 kg/m2 or higher (OR, 2.74; 95% CI, 1.76-4.27; p < 0.001) and those undergoing a unilateral procedure (OR, 1.99; 95% CI, 1.29-3.09; p = 0.002). Greater satisfaction was associated with receiving adequate information about surgical options (OR, 0.48; 95% CI, 0.32-0.69; p < 0.0001) and having a surgeon with a specialized breast surgery practice (OR, 0.56; 95% CI, 0.38-0.81; p = 0.002). CONCLUSIONS: Most patients undergoing mastectomy alone are satisfied with their surgical outcome. Surgeons may optimize patient experience by recognizing and supporting a patient's decision to go flat.

Assessing the Burden of Nodal Disease for Breast Cancer Patients with Clinically Positive Nodes: Hope for More Limited Axillary Surgery.

BACKGROUND: Omission of axillary lymph node dissection (ALND) is accepted for patients with one or two positive sentinel nodes, and studies are focusing on clinically node-positive patients who have been downstaged with neoadjuvant chemotherapy (NAC). Evidence is lacking for patients with positive nodes who undergo surgery upfront. These patients are assumed to have a higher burden of nodal disease such that ALND remains the standard of care. METHODS: Patients who underwent ALND for breast cancer between 2010 and 2019 at the authors' institution were retrospectively identified. Those with clinical N1 disease were included in the study. Patients who received NAC and those who had surgery for sentinel node positive disease or axillary recurrence were excluded. Clinical and pathologic factors associated with nodal stage were evaluated. RESULTS: Of 111 patients who met the inclusion criteria, 61.3% had a palpable node on exam, and 41.4% ultimately had pN1 disease. Most of the tumors were estrogen receptor (ER)-positive (91.5%), and 21.7% of the tumors were invasive lobular cancers. Lobular histology, tumor size, and metastasis size were associated with higher nodal stage. In the multivariable analysis, the patients with nodal metastasis larger than 10 mm had significantly lower odds of having pN1 disease (odds ratio 0.12; 95% confidence interval 0.02-0.69; p = 0.02). In a subset analysis of patients with palpable nodes, tumor size and histology remained significantly associated with nodal stage. CONCLUSION: More than 40% of breast cancer patients with clinically positive nodes had minimal nodal disease (pN1) at surgery. Additionally, palpable nodes on exam did not predict higher nodal stage. A subset of patients with clinically positive nodes may be identified who can potentially be spared the morbidity of ALND.

A comparison of two non-radioactive alternatives to wire for the localization of non-palpable breast cancers.

PURPOSE: Multiple wire-free technologies for localization of non-palpable breast cancers have emerged as satisfactory alternatives to wire. However, no study has compared two non-radioactive wire-free approaches to one another. The purpose of this study was to compare outcomes among LOCalizer™ radiofrequency identification (RFID), SAVI Scout® (SAVI), and wire localization (WL). METHODS: This was a retrospective, cross-sectional cohort study of patients undergoing lumpectomy for non-palpable breast cancer at a single institution between August 2017 and February 2019. Patients were divided into three cohorts based on localization technique: RFID, SAVI or WL. Operative times and average tumor volumes were compared using one-way analysis of variance. Positive margin and re-excision rates were compared with Fisher's exact test. RESULTS: Among 104 patients who underwent lumpectomy for non-palpable breast cancer, 33 patients (31.7%) had RFID, 21 (20.2%) had SAVI, and 50 (48.0%) had WL. Operative times were 79 min for RFID, 81 min for SAVI, and 78 min for WL (p = 0.91). Volume of tissue resected was 36.3 cm3, 31.7 cm3, and 35.3 cm3 for RFID, SAVI, and WL, respectively (p = 0.84). Positive margin rates (RFID 3.0% vs SAVI 9.5% vs WL 8.0%, p = 0.67) and re-excision rates (RFID 6.1% vs SAVI 9.5% vs WL 10.0%, p = 0.82) were similar across groups. CONCLUSIONS: Wire-free localization technologies have been compared to WL demonstrating similar efficacy. Our study suggests that RFID and SAVI Scout also perform similarly to one another. Physicians and institutions may consider more nuanced features of each localization system rather than performance alone when choosing a wire-free alternative.

National Trends in Immediate Breast Reconstruction: An Analysis of Implant-Based Versus Autologous Reconstruction After Mastectomy.

BACKGROUND: Many factors affect access to immediate breast reconstruction (IR) after mastectomy. The present study was performed to assess trends, outcomes, and predictors of IR techniques using a nationally representative cohort. METHODS: The 2009-2014 National Inpatient Sample (NIS) was used to identify adult women who underwent inpatient mastectomy with IR. Patients were compared by type of reconstruction: implant-based IR versus autologous reconstruction (AR). AR was classified as a microsurgical or pedicled flap procedure. Incidence, outcomes, and predictors were assessed using Chi squared univariate tests and multivariable logistic regression analyses. RESULTS: Of 194,073 women who underwent IR, 136,668 (70.4%) received implant-based IR and 57,405 (29.6%) received AR. Of those who underwent AR procedures, 31,336 (54.6%) received microsurgical flaps and 26,680 (46.5%) received pedicled flaps. Utilization of deep inferior epigastric perforator (DIEP) flaps increased significantly (28.6-42.5% of AR, P < 0.001). Predictors of AR were Black race [adjusted odds ratio (AOR) = 1.46, P < 0.001], lower Elixhauser Comorbidity Index (AOR = 1.25, P < 0.001), private insurance (AOR = 1.07, P = 0.030), body mass index (BMI) ≥ 30 kg/m2 (AOR = 1.38, P < 0.001), urban teaching hospital designation (AOR = 1.77, P < 0.001), and high hospital volume (AOR = 3.11, P < 0.001). Similar factors were associated with the use of microsurgical flaps. AR and microsurgical flaps were associated with higher rates of acute inpatient complications, resource utilization and length of stay (LOS) compared with implant-based IR and pedicled flaps, respectively. CONCLUSION: Implant-based IR remains the most common type of IR, although rates of microsurgical AR are on the rise. Follow-up of complications, costs, and quality-of-life measures may show that AR provides long-term high-value care despite upfront morbidity, cost, and use of hospital resources.

Microchipping the breast: an effective new technology for localizing non-palpable breast lesions for surgery.

PURPOSE: Use of a wire to localize a non-palpable breast lesion for surgery is standard but archaic. We sought to evaluate a new radiofrequency localization system (RFLS) as an effective, non-radioactive alternative to the wire. METHODS: Patients who required surgical excision of a non-palpable breast lesion were consented for the study. Patients underwent localization with a radiofrequency Tag and surgical removal guided by the handheld LOCalizer probe. The primary study endpoint was successful placement and retrieval of the Tag, and secondary endpoints included marker migration; days prior to surgery of Tag insertion; patient, radiologist, and surgeon experience; distance of Tag from skin; and positive margin and re-excision rates for cancer. RESULTS: Fifty patients had successful placement and retrieval of the radiofrequency Tag. Likert questionnaire data revealed that most patients thought the procedure went smoothly and was easier than expected. Radiologists and surgeons thought that the Tag was as reliable as the wire. Of the 33 patients who had surgery for in situ or invasive cancer, one had a positive margin on final pathology (3%) and two underwent re-excision (6%). CONCLUSIONS: Data from this pilot study suggest that the RFLS is an effective localization system for non-palpable breast lesions intended for surgical removal. Unlike most other technologies, the LOCalizer probe detects distance from the Tag, and this unique feature may have contributed to the low positive margin rate seen in this study. The RFLS appears to offer advantages over current localization procedures and should be explored as an alternative to wire. ClinicalTrials.gov Identifier: NCT03202472.

Clinicopathological Features of Triple-Negative Breast Cancer Epigenetic Subtypes.

BACKGROUND/OBJECTIVE: Triple-negative breast cancer (TNBC) is a heterogeneous collection of breast tumors with numerous differences including morphological characteristics, genetic makeup, immune-cell infiltration, and response to systemic therapy. DNA methylation profiling is a robust tool to accurately identify disease-specific subtypes. We aimed to generate an epigenetic subclassification of TNBC tumors (epitypes) with utility for clinical decision-making. METHODS: Genome-wide DNA methylation profiles from TNBC patients generated in the Cancer Genome Atlas project were used to build machine learning-based epigenetic classifiers. Clinical and demographic variables, as well as gene expression and gene mutation data from the same cohort, were integrated to further refine the TNBC epitypes. RESULTS: This analysis indicated the existence of four TNBC epitypes, named as Epi-CL-A, Epi-CL-B, Epi-CL-C, and Epi-CL-D. Patients with Epi-CL-B tumors showed significantly shorter disease-free survival and overall survival [log rank; P = 0.01; hazard ratio (HR) 3.89, 95% confidence interval (CI) 1.3-11.63 and P = 0.003; HR 5.29, 95% CI 1.55-18.18, respectively]. Significant gene expression and mutation differences among the TNBC epitypes suggested alternative pathway activation that could be used as ancillary therapeutic targets. These epigenetic subtypes showed complementarity with the recently described TNBC transcriptomic subtypes. CONCLUSIONS: TNBC epigenetic subtypes exhibit significant clinical and molecular differences. The links between genetic make-up, gene expression programs, and epigenetic subtypes open new avenues in the development of laboratory tests to more efficiently stratify TNBC patients, helping optimize tailored treatment approaches.

Predictors associated with MRI surveillance screening in women with a personal history of unilateral breast cancer but without a genetic predisposition for future contralateral breast cancer.

PURPOSE: For women with a personal history of breast cancer (PHBC), no validated mechanisms exist to calculate future contralateral breast cancer (CBC) risk. The Manchester risk stratification guidelines were developed to evaluate CBC risk in women with a PHBC, primarily for surgical decision making. This tool may be informative for the use of MRI screening, as CBC risk is an assumed consideration for high-risk surveillance. METHODS: Three hundred twenty-two women with a PHBC were treated with unilateral surgery within our multidisciplinary breast clinic. We calculated lifetime CBC risk using the Manchester tool, which incorporates age at diagnosis, family history, genetic mutation status, estrogen receptor positivity, and endocrine therapy use. Univariate and multivariate logistic regression analyses (UVA/MVA) were performed, evaluating whether CBC risk predicted MRI surveillance. RESULTS: For women with invasive disease undergoing MRI surveillance, 66% had low, 23% above-average, and 11% moderate/high risk for CBC. On MVA, previous mammography-occult breast cancer [odds ratio (OR) 18.95, p < 0.0001], endocrine therapy use (OR 3.89, p = 0.009), dense breast tissue (OR 3.69, p = 0.0007), mastectomy versus lumpectomy (OR 3.12, p = 0.0041), and CBC risk (OR 3.17 for every 10% increase, p = 0.0002) were associated with MRI surveillance. No pathologic factors increasing ipsilateral breast cancer recurrence were significant on MVA. CONCLUSIONS: Although CBC risk predicted MRI surveillance, 89% with invasive disease undergoing MRI had <20% calculated CBC risk. Concerns related to future breast cancer detectability (dense breasts and/or previous mammography-occult disease) predominate decision making. Pathologic factors important for determining ipsilateral recurrence risk, aside from age, were not associated with MRI surveillance.