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Aims: Radial sclerosing lesions (RSLs) are benign breast lesions composed of glandular and epithelial proliferations with stellate architecture and fibro‐elastotic stroma, which can mimic invasive carcinoma on imaging. Surgical management following a core biopsy diagnosis of RSLs remains controversial. Methods and results: We retrospectively identified core biopsies with RSLs without atypia who underwent subsequent surgical excision between 2015 and 2021. All core biopsy slides were reviewed to confirm the diagnosis. Imaging was reviewed to determine radiological–pathological concordance. An upgrade was defined as invasive carcinoma or ductal carcinoma in situ (DCIS) in the excision. The final cohort consisted of 130 core biopsies from 124 women (median age = 52 years, range = 27–76). The imaging modality was mammogram in 52 (40%) cases, MRI in 52 (40%) and ultrasound in 26 (20%). One hundred and seven (82%) core biopsies were vacuum‐assisted and 23 (18%) were ultrasound‐guided without vacuum assistance. The median lesion size on imaging was 9 mm (range = 2–41). Overall, two (1%) cases were upgraded at excision, including one microinvasive lobular carcinoma and one 2 mm focus of invasive mammary carcinoma with associated DCIS. In both cases, the upgraded foci of carcinoma were not closely associated with the biopsy site and were considered incidental upgrades. Conclusions: This study adds to the body of literature supporting observation, rather than routine excision of radial sclerosing lesions without atypia. [ABSTRACT FROM AUTHOR]

The current histological classification of in‐situ and invasive lobular carcinomas (ILCs) includes different morphological variants, some of which have been recently described. In this review, we will focus upon: (i) the diagnostic criteria of non‐invasive lobular neoplasia and treatment implications across different countries; (ii) utility and limitations of immunohistochemistry; (iii) recently described variants of ILC; and (iv) the significance of lobular differentiation in invasive carcinoma for clinical management. [ABSTRACT FROM AUTHOR]

The cover image is based on the Original Article Radial sclerosing lesions found on core needle biopsy: excision can be safely avoided by Anne Grabenstetter et al., https://doi.org/10.1111/his.15233..By Anne Grabenstetter; Sandra B Brennan; Maxine S Jochelson; Edi Brogi; Monica Morrow; Lee K Tan and Timothy M D'AlfonsoReported by Author; Author; Author; Author; Author; Author; Author [Extracted from the article]

Aims: Radiation‐associated angiosarcomas (RT‐ASs) of the breast are rare tumours with a poor prognosis. MYC gene amplification is considered to be the hallmark of RT‐AS, and is sometimes used as a diagnostic tool to distinguish it from other radiation‐associated vascular lesions. However, a small subset of RT‐ASs lacks MYC amplification, and this may be associated with better outcome. Loss of trimethylation at lysine 27 of histone 3 (H3K27me3) expression by immunohistochemistry (IHC) has been recently postulated as an additional diagnostic marker for RT‐AS. The aims of this study were to evaluate the impact of MYC amplification as detected by fluorescence in‐situ hybridisation and/or next‐generation sequencing on clinicopathological features and outcome in a large cohort of RT‐ASs, compare outcome with those of radiation‐associated sarcomas (RT‐Ss) of the breast other than angiosarcoma, and evaluate expression of H3K27me3 IHC in these groups. Methods and results: Eighty‐one RT‐ASs were identified, including 73 that were MYC‐amplified and 8 (10%) that were MYC‐non‐amplified. MYC‐amplified RT‐ASs were diagnosed in older patients (median age, 69 years versus 61 years). The 5‐year disease‐specific survival and 5‐year overall survival rates were 56% and 47%, respectively. Older age, larger tumour size, positive margin and MYC amplification were associated with worse prognosis. None of the RT‐ASs showed complete loss of H3K27me3 IHC expression. All 18 RT‐Ss were MYC‐non‐amplified, and complete loss of H3K27me3 expression was seen in 2 cases. We found no difference in prognosis between RT‐AS and RT‐S. Conclusions: RT‐AS of the breast is associated with a poor prognosis. Older age at diagnosis, larger tumour size, positive margin at excision and MYC amplification are associated with worse prognosis. [ABSTRACT FROM AUTHOR]

Metaplastic breast carcinoma (MBC) and uterine carcinosarcoma (UCS) are rare aggressive cancers, characterized by an admixture of adenocarcinoma and areas displaying mesenchymal/sarcomatoid differentiation. We sought to define whether MBCs and UCSs harbor similar patterns of genetic alterations, and whether the different histologic components of MBCs and UCSs are clonally related. Whole‐exome sequencing (WES) data from MBCs (n = 35) and UCSs (n = 57, The Cancer Genome Atlas) were reanalyzed to define somatic genetic alterations, altered signaling pathways, mutational signatures, and genomic features of homologous recombination DNA repair deficiency (HRD). In addition, the carcinomatous and sarcomatous components of an additional cohort of MBCs (n = 11) and UCSs (n = 6) were microdissected separately and subjected to WES, and their clonal relatedness was assessed. MBCs and UCSs harbored recurrent genetic alterations affecting TP53, PIK3CA, and PTEN, similar patterns of gene copy number alterations, and an enrichment in alterations affecting the epithelial‐to‐mesenchymal transition (EMT)‐related Wnt and Notch signaling pathways. Differences were observed, however, including a significantly higher prevalence of FAT3 and FAT1 somatic mutations in MBCs compared to UCSs, and conversely, UCSs significantly more frequently harbored somatic mutations affecting FBXW7 and PPP2R1A as well as HER2 amplification than MBCs. Genomic features of HRD and biallelic alterations affecting bona fide HRD‐related genes were found to be more prevalent in MBCs than in UCSs. The distinct histologic components of MBCs and UCSs were clonally related in all cases, with the sarcoma component likely stemming from a minor subclone of the carcinoma component in the samples with interpretable chronology of clonal evolution. Despite the similar histologic features and pathways affected by genetic alterations, UCSs differ from MBCs on the basis of FBXW7 and PPP2R1A mutations, HER2 amplification, and lack of HRD, supporting the notion that these entities are more than mere phenocopies of the same tumor type in different anatomical sites. [ABSTRACT FROM AUTHOR]

Aims: The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) updated the testing guideline in 2018 to address issues arising from uncommon human epidermal growth factor receptor 2 (HER2) fluorescence in‐situ hybridisation (FISH) results according to the 2013 guideline. Next‐generation sequencing (NGS) may be used to better classify patients. The aim of this study was to assess the ERBB2 amplification status of invasive breast carcinoma with equivocal HER2 immunohistochemistry (IHC) results by using NGS, focusing on Group 4 (HER2/CEP17 ratio of <2.0; average HER2 signals/cell of ≥4.0 and <6.0). Methods and results: We retrospectively reviewed HER2 FISH and NGS data of HER2 IHC‐equivocal breast carcinomas at our centre between January 2009 and September 2019, wherein all three assays were performed on the same tissue block, and compared HER2 FISH results, according to the 2018 ASCO/CAP guideline, and the ERBB2 amplification status determined with NGS. A total of 52 HER2 FISH and NGS results from 51 patients with HER2 IHC‐equivocal breast carcinomas were reviewed. The cohort included eight cases classified as 2018 ASCO/CAP in‐situ hybridisation Group 1, three classified as Group 2, three classified as Group 3, 14 classified as Group 4, and 24 classified as Group 5. Thirteen of 14 (92.9%) Group 4 (HER2‐negative) cases were classified as ERBB2‐non‐amplified by the use of NGS; the discordant case was later classified as Group 1 with alternative sample FISH testing. NGS revealed no significant difference in somatic mutations or copy number alterations between Groups 4 and 5. Conclusions: Our NGS findings support the reclassification of HER2 FISH‐equivocal cases as HER2‐negative under the 2018 ASCO/CAP guideline. [ABSTRACT FROM AUTHOR]

Juvenile papillomatosis (JP) of the breast is a rare benign mass‐forming lesion occurring in young women, which is histologically characterized by a constellation of proliferative changes and large cysts, giving it the gross appearance of Swiss cheese. A subset of patients with JP report a family history of breast carcinoma and/or coexisting or subsequent breast carcinoma. We performed whole‐exome sequencing of the hyperplastic epithelial component of three JPs, including one with coexisting ductal carcinoma in situ (DCIS) and invasive ductal carcinoma of no special type (IDC‐NST). JPs harbored clonal somatic PIK3CA hotspot mutations in two cases. In the JP with coexisting DCIS and IDC‐NST, these lesions were clonally related to the associated JP, sharing a clonal PIK3CA E542K somatic hotspot mutation. JP showed a paucity of copy number alterations, whereas the associated DCIS and IDC‐NST showed concurrent 1q gains/16q losses, hallmarks of estrogen receptor (ER)‐positive breast cancers. We observed JP to harbor a dominant aging‐related mutational signature, whereas coexisting DCIS and IDC‐NST showed greater exposure to an APOBEC signature. Taken together, our findings suggest that, at least in a subset of cases, JP might constitute the substrate from which DCIS and invasive breast carcinomas develop. [ABSTRACT FROM AUTHOR]

Aims: Metaplastic breast carcinoma (MBC) is a rare type of triple‐negative breast cancer that shows vast histological and genetic heterogeneity. Osseous differentiation can be found in different subtypes of MBC. Whether MBCs with osseous differentiation are underpinned by specific genetic alterations has yet to be defined. The aim of this study was to investigate the repertoire of somatic mutations and copy number alterations (CNAs) in three MBCs with extensive osseous differentiation. Methods and results: Tumour and normal DNA samples from three MBCs with extensive osseous differentiation were subjected to whole‐exome sequencing. Somatic mutations, CNAs and mutational signatures were determined by use of a validated bioinformatics pipeline. Our analyses revealed clonal TP53 hotspot mutations associated with loss of heterozygosity of the wild‐type allele coupled with mutations affecting genes related to the Wnt and/or the phosphoinositide 3‐kinase–AKT–mammalian target of rapamycin pathways in all cases analysed. All cases showed a dominant mutational signature 1, with two cases showing a secondary signature 3 in addition to other features of homologous recombination DNA repair defects. The oncostatin M receptor gene, which plays a role in mesenchymal differentiation and bone formation, was found to be mutated in two MBCs with extensive osseous differentiation and in none of 35 previously published 35 MBCs. Conclusion: Our findings suggest that MBCs with osseous differentiation have somatic mutations similar to those of other forms of MBC. [ABSTRACT FROM AUTHOR]

The designation of noninvasive lobular neoplasia applies to atypical epithelial proliferations composed of noncohesive cells secondary to loss or functional alteration of E‐cadherin‐mediated cell adhesion. The morphologic spectrum of noninvasive lobular neoplasia encompasses atypical lobular hyperplasia (ALH) and classic lobular carcinoma in situ (classic LCIS) and two LCIS variants, namely florid LCIS (F‐LCIS) and pleomorphic LCIS (P‐LCIS), as defined in the World Health Organization (WHO) Classification of Tumors of the Breast 5th ed. Herein, we review the morphologic, immunohistochemical, and molecular features of noninvasive lobular neoplasia, with special emphasis on F‐LCIS and P‐LCIS. We also review imaging features, management at core needle biopsy, upgrade rates at surgical excision, and clinical management dilemmas. [ABSTRACT FROM AUTHOR]

Aims: Breast adenomyoepitheliomas (AMEs) are uncommon tumours. Most oestrogen receptor (ER)‐positive AMEs have mutations in phosphoinositide 3‐kinase (PI3K) pathway genes, whereas ER‐negative AMEs usually harbour concurrent mutations affecting the HRAS Q61 hotspot and PI3K pathway genes. Here, we sought to determine the sensitivity and specificity of RAS Q61R immunohistochemical (IHC) analysis for detection of HRAS Q61R mutations in AMEs. Methods and results: Twenty‐six AMEs (14 ER‐positive; 12 ER‐negative) previously subjected to massively parallel sequencing (n = 21) or Sanger sequencing (n = 5) of the HRAS Q61 hotspot locus were included in this study. All AMEs were subjected to IHC analysis with a monoclonal (SP174) RAS Q61R‐specific antibody, in addition to detailed histopathological analysis. Nine ER‐negative AMEs harboured HRAS mutations, including Q61R (n = 7) and Q61K (n = 2) mutations. Five of seven (71%) AMEs with HRAS Q61R mutations were immunohistochemically positive, whereas none of the AMEs lacking HRAS Q61R mutations (n = 17) were immunoreactive. RAS Q61R immunoreactivity was restricted to the myoepithelium in 80% (4/5) of cases, whereas one case showed immunoreactivity in both the epithelial component and the myoepithelial component. RAS Q61R immunohistochemically positive AMEs were associated with infiltrative borders (P < 0.001), necrosis (P < 0.01) and mitotic index in the epithelial (P < 0.05) and myoepithelial (P < 0.01) components. RAS Q61R IHC assessment did not reveal Q61K mutations (0/2). Conclusions: IHC analysis of RAS Q61R shows high specificity (100%) and moderate sensitivity (71%) for detection of HRAS Q61R mutations in breast AMEs, and appears not to detect HRAS Q61K mutations. IHC analysis of RAS Q61R may constitute a useful technique in the diagnostic workup of ER‐negative AMEs. [ABSTRACT FROM AUTHOR]

The 8th edition of the American Joint Committee on Cancer (AJCC) staging guidelines combine traditional TNM system with biomarkers to reflect our current understanding of tumor biology and targeted therapy. In this study, we investigated the impact of the TNM + Biomarkers staging system and the additive value of Oncotype Dx™ genomic profile recurrence score (RS) (TNM + Biomarkers+RS <11) for the staging of breast cancer (BC) using data from two tertiary referral cancer centers. Compared to TNM alone, the TNM + Biomarkers system changed the stage group in 32.7% of BCs (27% downstage, 5.7% upstage). Most (98.3%) of the downstaged BCs were estrogen receptor (ER)+/progesterone receptor (PR)+, whereas 78% of the upstaged BCs were ER−/PR−/human epidermal growth factor receptor 2 (HER2)−. Compared to TNM + Biomarkers staging, the addition of genetic profile data (TNM + Biomarker+RS <11) downstaged only <1% BCs. Our analysis suggests that for T1‐T2N0 ER+/HER2− BCs, Oncotype Dx™ RS <11 provides added value as a staging parameter only in a very small group of cases compared to TNM + Biomarkers alone. [ABSTRACT FROM AUTHOR]

Aims: Secretory carcinoma of the breast (SCB) is a rare histological type of breast carcinoma with a generally indolent clinical behaviour. We aim to elucidate the clinical, pathological and molecular findings of SCB cases and identify characteristics associated with aggressive clinical courses. Methods and results: Fourteen patients with SCB were identified, including 12 women and two men, with a median age of 56 years (range = 8–81 years). Clinical data, histological diagnosis, molecular findings and follow‐up were reviewed. Eight patients presented with palpable masses and four patients with radiographic abnormalities. All cases were unilateral. Surgical procedures included excisional biopsies and ipsilateral mastectomies. In 10 cases, oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) results were obtained, with six cases positive for ER and three positive for PR. All cases lacked HER2 overexpression. Sentinel lymph node biopsy was performed in 10 cases, and two patients had axillary lymph node metastasis. Follow‐up ranged from 21 to 212 months (median = 70 months). Two patients developed distant metastasis of SCB. Molecular analysis of these aggressive tumours revealed amplification of the 16p13.3 locus, a TERT promotor mutation and loss of 9p21.3 locus. Review of the literature for SCB cases with distant metastasis was performed. Conclusions: Although SCBs are generally associated with a favourable prognosis, our study and review demonstrate that a subset of SCBs may develop distant metastases. Further studies are warranted to identify markers predictive of more aggressive clinical behaviour in this rare breast cancer subtype. [ABSTRACT FROM AUTHOR]

Aims: Micropapillary variant of mucinous carcinoma of the breast (MPMC) is a rare histological form of oestrogen receptor (ER)‐positive invasive carcinoma that is characterised by micropapillary clusters of tumour cells in lakes of extracellular mucin. The aims of this study were to determine the genetic alterations underpinning MPMCs, and to determine whether they overlap with those of mucinous carcinomas and/or invasive micropapillary carcinomas. Methods and results: DNA from five MPMCs was subjected to whole‐exome sequencing. Somatic mutations, copy number alterations and mutational signatures were determined with state‐of‐the‐art bioinformatics methods. No mutations in genes significantly mutated in breast cancer, including TP53,PIK3CA,GATA3, and MAP3K1, were detected. We identified copy number alterations that have been reported in invasive micropapillary carcinomas, such as recurrent gains in 1q, 6p, 8q, and 10q, and recurrent losses in 16q, 11q, and 13q, as well as a recurrent 8p12–8p11.2 amplification encompassing FGFR1. Like mucinous carcinomas, three of the five MPMCs analysed lacked PIK3CA mutations, 1q gains, and 16q losses, which are the hallmark genetic alterations of ER‐positive breast cancers, whereas two MPMCs harboured 16q losses and/or a complex pattern of copy number alterations similar to those found in breast‐invasive micropapillary carcinomas. Conclusions: MPMCs are heterogeneous at the genetic level; some tumours show a pattern of somatic genetic alterations similar to those of mucinous carcinomas, whereas others resemble invasive micropapillary carcinomas at the genetic level. These findings suggest that MPMCs may not constitute one histological subtype, but rather a convergent phenotype that can stem from mucinous carcinomas or invasive micropapillary carcinomas. [ABSTRACT FROM AUTHOR]

Aims: Solid papillary breast carcinoma resembling the tall cell variant of papillary thyroid neoplasms (BPTC), also known as solid papillary carcinoma with reverse polarity, is a rare histological type of breast cancer that resembles morphologically the tall cell variant of papillary thyroid carcinoma. BPTCs are characterised by IDH2 R172 hotspot somatic mutations or mutually exclusive TET2 somatic mutations, concurrently with mutations affecting PI3K pathway‐related genes. We sought to characterise their histology and investigate the frequency of IDH2 and PIK3CA mutations in an independent cohort of BPTCs, as well as in conventional solid papillary carcinomas (SPCs). Methods and results: Six BPTCs, not previously analysed molecularly, and 10 SPCs were reviewed centrally. Tumour DNA was extracted from microdissected histological sections and subjected to Sanger sequencing of the IDH2 R172 hotspot locus and exons 9 and 20 of PIK3CA. All six BPTCs were characterised by solid, papillary and follicular architecture with circumscribed, invasive tumour nodules composed of epithelial cells with reverse polarity. IDH2 mutations were identified in all six BPTCs (three R172S, two R172T and one R172G), four of which also harboured PIK3CA mutations (two H1047R, one Q546K and one Q546R). By contrast, all SPCs lacked IDH2 mutations, while one of 10 harboured a PIK3CA mutation (H1047R). Conclusion: We validated the presence of IDH2 R172 hotspot mutations and PIK3CA hotspot mutations in 100% and 67% BPTCs tested, respectively, and documented absence of IDH2 R172 mutations in SPCs. These findings confirm the genotypical–phenotypical correlation reported previously in BPTC, which constitutes an entity distinct from conventional SPC. [ABSTRACT FROM AUTHOR]

Aims Surgical excision of all benign vascular lesions of the breast identified by core needle biopsy has been recommended in the past to rule out a more serious lesion. In this study we investigated the clinical, radiological and pathological findings in patients diagnosed with a benign vascular lesion at our institution to assess whether excision may be spared for lesions without atypia. Methods and results We searched the electronic medical record for patients with a vascular lesion of the breast diagnosed between 2000 and 2015. The study population consisted of 84 patients, 83 females and one male. The index diagnoses included 76 benign vascular lesions, five vascular lesions with cytological atypia and three angiosarcomas. A radiologist reviewed all pre- and post-biopsy imaging studies; all cases had concordant radiological and pathological findings. Based on radiological and histological correlation, the vascular lesion accounted for the radiological target in 40 (48%) cases and was deemed an incidental finding in 44 (52%). Seven of 32 (22%) targeted and 10 of 44 (23%) incidental benign vascular lesions underwent surgical excision; there were no upgrades at excision. No recurrences or clinical events were observed in patients with a targeted or incidental benign vascular lesion with a median follow-up of 39 months and 40.6 months, respectively. Conclusion Our data suggest that benign vascular lesions diagnosed on core biopsy with concordant radiological and pathological findings do not warrant surgical excision. [ABSTRACT FROM AUTHOR]

Aims Breast myxoid fibroadenomas ( MFAs) are characterized by a distinctive hypocellular myxoid stroma, and occur sporadically or in the context of Carney complex, an inheritable condition caused by PRKAR1A-inactivating germline mutations. Conventional fibroadenomas ( FAs) are underpinned by recurrent MED12 mutations in the stromal components of the lesions. The aim of this study was to investigate the genomic landscape of MFAs and compare it with that of conventional FAs. Methods and results Eleven MFAs from patients without clinical and/or genetic evidence of Carney complex were retrieved. DNA samples of tumour and matching normal tissue were subjected to massively parallel sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets ( MSK- IMPACT) assay, an assay targeting 410 cancer genes. Genetic alterations detected by MSK- IMPACT were tested in samples in which the stromal and epithelial components were separately laser capture-microdissected. Sequencing revealed no germline PRKAR1A mutations and non-synonymous mutations in six MFAs. Interestingly, in three of the MFAs in which the stromal and epithelial components were separately microdissected, the mutations were found to be restricted to the epithelial rather than the stromal component. The sole exception was a lesion harbouring a somatic truncating PRKAR1A mutation. Upon histological re-review, this case was reclassified as a breast myxoma, consistent with the spectrum of tumous observed in Carney complex patients. In this case, the PRKAR1A somatic mutation was restricted to the stromal component. Conclusion MFAs lack MED12 mutations, and their stromal components seem not to harbour mutations in the 410 cancer genes tested. Whole-exome and/or whole-genome analyses of MFAs are required to elucidate their genetic drivers. [ABSTRACT FROM AUTHOR]

The consequences of patient identification errors due to specimen mislabeling can be deleterious. We describe two near-miss events involving mislabeled breast specimens from two patients who sought treatment at our institution. In both cases, microscopic review of the slides identified inconsistencies between the histologic findings and patient age, unveiling specimen identification errors. By correlating the clinical information with the microscopic findings, we identified mistakes that had occurred at the time of specimen accessioning at the original laboratories. In both cases, thanks to a timely reassignment of the specimens, the patients suffered no harm. These cases highlight the importance of routine clinical and pathologic correlation as a critical component of quality assurance and patient safety. A review of possible specimen identification errors in the anatomic pathology setting is presented. [ABSTRACT FROM AUTHOR]

Uterine adenosarcomas and breast phyllodes tumors (PTs) are morphologically similar, being composed of stromal projections in a leaf-like fashion lined by epithelial cells. Here, we investigated whether their histologic similarities would be mirrored at the genetic level. The previously reported repertoires of somatic genetic alterations found in 19 adenosarcomas and 22 PTs (six benign, six borderline, and 10 malignant) were compared. PTs significantly more frequently displayed mutations affecting MED12, the TERT gene promoter and bona fide cancer genes, whereas adenosarcomas harbored a higher rate of MDM2/CDK4 and TERT gene amplifications. Pathway analyses based on the genes affected by somatic genetic alterations in these tumors indicated that Wnt signaling likely plays a role in the biology of adenosarcomas and benign/borderline PTs. In conclusion, despite the differences at the gene level, PTs and adenosarcomas share remarkable morphologic similarities and enrichment for somatic genetic alterations affecting Wnt pathway-related genes. [ABSTRACT FROM AUTHOR]

Homologous recombination (HR) DNA repair-deficient (HRD) breast cancers have been shown to be sensitive to DNA repair targeted therapies. Burgeoning evidence suggests that sporadic breast cancers, lacking germline BRCA1/ BRCA2 mutations, may also be HRD. We developed a functional ex vivo RAD51-based test to identify HRD primary breast cancers. An integrated approach examining methylation, gene expression, and whole-exome sequencing was employed to ascertain the aetiology of HRD. Functional HRD breast cancers displayed genomic features of lack of competent HR, including large-scale state transitions and specific mutational signatures. Somatic and/or germline genetic alterations resulting in bi-allelic loss-of-function of HR genes underpinned functional HRD in 89% of cases, and were observed in only one of the 15 HR-proficient samples tested. These findings indicate the importance of a comprehensive genetic assessment of bi-allelic alterations in the HR pathway to deliver a precision medicine-based approach to select patients for therapies targeting tumour-specific DNA repair defects. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Fibroepithelial lesions ( FELs) are the most frequent breast tumors in adolescent females. The pubertal hormonal surge could impact the growth and microscopic appearance of FELs in this age group. In this study, we evaluate the morphology and clinical behavior of FELs in adolescents. We searched the 1992-2012 pathology data base for FELs in females 18 years old or younger (F ≤18 years). Seven FELs from 1975 to 1983 were also included. Three pathologists reviewed all available material. Patient (pt) characteristics and follow-up information were obtained from electronic medical records. Forty-eight F ≤18 years had 54 FELs with available slides. Thirty (67%) pts were Caucasian, 12 (27%) African-American, two (4%) Hispanic, one (2%) Asian; three were of unknown race/ethnicity. Median age at diagnosis was 16 years. Median age at menarche was 12 years; most (96%) FELs occurred after menarche (median interval 48 months). All patients underwent lumpectomy; one required subsequent mastectomy. The FELs were 34 fibroadenomas ( FAs) (11 usual, 23 juvenile), and 20 phyllodes tumors ( PTs) (16 benign, one borderline and three malignant). Eight (35%) juvenile FAs showed slight intratumoral heterogeneity. The mean mitotic rate was 1.3 mitoses/10 high-power fields ( HPFs) (range, 0-6) in usual FAs, 1.8/10 HPFs in juvenile FAs, 3.1/10 HPFs in benign PTs, 10/10 HPFs in the borderline PT and 17/10 HPFs in malignant PTs. The mean follow-up for 29 pts with 33 FELs was 44 months. Two (10%) PTs recurred locally (a benign PT at 18 months, and a borderline PT at 11 months). Both recurrent PTs had microscopic margins <1 mm. Mitotic activity in FAs from adolescents can be substantial and this finding should be interpreted cautiously. Awareness of the morphologic features of FELs in adolescents is important to avoid overdiagnosis of PTs, which can lead to additional unnecessary and potentially disfiguring surgery. [ABSTRACT FROM AUTHOR]

BACKGROUND A 21-gene expression assay (Oncotype DX recurrence score [RS]) that uses reverse transcriptase-polymerase chain reaction is used clinically in patients with early-stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast carcinoma (ER+/HER2- BC) to determine both prognosis with tamoxifen therapy and the usefulness of adding adjuvant chemotherapy. Use of the assay is associated with reductions in overall chemotherapy use. The current study examined the treatments and outcomes in patients with low RS. METHODS The authors reviewed the institutional database to identify patients with lymph node-negative, ER+/HER2- BC who were treated at the study institution between September 2008 and August 2013 and their 21-gene RS results. RESULTS A total of 1406 consecutive patients with lymph node-negative ER+/HER2- BC and a low RS were identified (510 patients had an RS of 0-10 and 896 patients had an RS of 11-17). The median age at the time of diagnosis of BC was 56 years; 63 patients (4%) were aged <40 years. Overall, 1361 patients (97%) received endocrine therapy and 170 patients (12%) received chemotherapy. The median follow-up was 46 months. Six patients (0.4%) developed distant metastases (1 patient with an RS of 5 and 5 patients with an RS of 11-17). In the cohorts of patients with an RS of 11 to 17, the absolute rate of distant metastasis among patients aged <40 years was 7.1% (3 of 42 patients) versus 0.2% among patients aged ≥40 years (2 of 854 patients). CONCLUSIONS The data from the current study document a 0.4% rate of distant metastasis within 5 years of BC diagnosis among patients with lymph node-negative ER+/HER2- BC with an RS <18. Patients aged <40 years at the time of BC diagnosis were observed to have a higher rate of distant metastases. Analysis of data from other studies is necessary to validate this observation further. Cancer 2017;131-137. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: The surgical management of mammary intraductal papilloma without atypia (IDP) identified at core-needle biopsy (CNB) is controversial. This study assessed the rate of upgrade to carcinoma at surgical excision (EXC).Methods: This study identified women with a CNB diagnosis of intraductal papilloma without atypia or carcinoma at a cancer center between 2003 and 2013. Radiologic-pathologic concordance was assessed for all cases, and discordant cases were excluded. The radiologic and clinicopathologic features of patients with a CNB diagnosis of IDP were correlated with an upgrade to carcinoma at EXC.Results: The study population consists of 189 women with 196 IDPs; 166 women (171 IDPs) underwent EXC. The upgrade rate was 2.3% (4 of 171). The upgraded lesions were 2 invasive lobular carcinomas and 2 cases of ductal carcinoma in situ (DCIS). One case of DCIS involved the residual IDP, whereas the other 3 carcinomas were ≥ 8 mm away. Twenty-four women (25 IDPs) did not undergo EXC and had stable imaging on follow-up (median, 23.5 months).Conclusions: The upgrade rate at EXC for IDPs diagnosed at CNB with radiologic-pathologic concordance was 2.3%. These findings suggest that observation is appropriate for patients with radiologic-pathologic concordant CNB yielding IDP, regardless of its size. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2819-2827. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Sentinel lymph node (SLN) biopsy has been established as the standard of care for axillary staging in patients with invasive breast carcinoma and clinically negative lymph nodes (cN0). Historically, all patients with a positive SLN underwent axillary lymph node dissection (ALND). The ACOSOG Z0011 trial showed that women with T1-T2 disease and cN0 who undergo breast-conserving surgery and whole-breast radiotherapy can safely avoid ALND. The main goal of SLN examination should be to detect all macrometastases (>2 mm). Gross sectioning of SLNs at 2-mm intervals and microscopic examination of one haematoxylin and eosin-stained section from each SLN block is the preferred method for pathological evaluation of SLNs. The role and timing of SLN biopsy for patients who have received neoadjuvant chemotherapy is controversial, and continues to be explored in clinical trials. SLN biopsies from patients with invasive breast carcinoma who have received neoadjuvant chemotherapy pose particular challenges for pathologists. [ABSTRACT FROM AUTHOR]

Phyllodes tumours constitute an uncommon but complex group of mammary fibroepithelial lesions. Accurate and reproducible grading of these tumours has long been challenging, owing to the need to assess multiple stratified histological parameters, which may be weighted differently by individual pathologists. Distinction of benign phyllodes tumours from cellular fibroadenomas is fraught with difficulty, due to overlapping microscopic features. Similarly, separation of the malignant phyllodes tumour from spindle cell metaplastic carcinoma and primary breast sarcoma can be problematic. Phyllodes tumours are treated by surgical excision. However, there is no consensus on the definition of an appropriate surgical margin to ensure completeness of excision and reduction of recurrence risk. Interpretive subjectivity, overlapping histological diagnostic criteria, suboptimal correlation between histological classification and clinical behaviour and the lack of robust molecular predictors of outcome make further investigation of the pathogenesis of these fascinating tumours a matter of active research. This review consolidates the current understanding of their pathobiology and clinical behaviour, and includes proposals for a rational approach to the classification and management of phyllodes tumours. [ABSTRACT FROM AUTHOR]

Aims Somatic mutations in exon 2 of the mediator complex subunit 12 ( MED12) gene have been identified in 60% of breast fibroadenomas (FAs). The aim of this study was to define whether phyllodes tumours (PTs) would harbour MED12 somatic mutations in a way akin to FAs. Methods and results A collection of 73 fibroepithelial tumours (including 26 FAs, 25 benign PTs, nine borderline PTs and 13 malignant PTs) from 64 patients was retrieved from the authors' institution. Sections from formalin-fixed paraffin-embedded (FFPE) blocks were microdissected to ensure an enrichment in neoplastic stromal elements of >70%. DNA samples extracted from tumour and matched normal tissues were subjected to Sanger sequencing of exon 2 of the MED12 gene. MED12 exon 2 somatic mutations, including 28 somatic single nucleotide variants and 19 insertions and deletions, were found in 65%, 88%, 78% and 8% of FAs, benign PTs, borderline PTs and malignant PTs, respectively. Malignant PTs harboured MED12 exon 2 somatic mutations significantly less frequently than FAs, benign and borderline PTs. Conclusions Although MED12 exon 2 somatic mutations probably constitute the driver genetic event of most FAs, benign and borderline PTs, our results suggest that the majority of malignant PTs may be driven by other genetic/epigenetic alterations. [ABSTRACT FROM AUTHOR]

Purpose Lobular carcinoma in situ (LCIS) is both a risk indicator and non-obligate precursor of invasive lobular carcinoma (ILC). We sought to characterize the transcriptomic features of LCIS and ILC, with a focus on the identification of intrinsic molecular subtypes of LCIS and the changes involved in the progression from normal breast epithelium to LCIS and ILC. Methods Fresh-frozen classic LCIS, classic ILC, and normal breast epithelium (N) from women undergoing prophylactic or therapeutic mastectomy were prospectively collected, laser-capture microdissected, and subjected to gene expression profiling using Affymetrix HG-U133A 2.0 microarrays. Results Unsupervised hierarchical clustering of 40 LCIS samples identified 2 clusters of LCIS distinguished by 6431 probe sets (p < 0.001). Genes identifying the clusters included proliferation genes and other genes related to cancer canonical pathways such as TGF beta signaling, p53 signaling, actin cytoskeleton, apoptosis and Wnt-Signaling pathway. A supervised analysis to identify differentially expressed genes (p < 0.001) between normal epithelium, LCIS, and ILC, using 23 patient-matched triplets of N, LCIS, and ILC, identified 169 candidate precursor genes, which likely play a role in LCIS progression, including PIK3R1, GOLM1, and GPR137B. These potential precursor genes map significantly more frequently to 1q and 16q, regions frequently targeted by gene copy number alterations in LCIS and ILC. Conclusion Here we demonstrate that classic LCIS is a heterogeneous disease at the transcriptomic level and identify potential precursor genes in lobular carcinogenesis. Understanding the molecular heterogeneity of LCIS and the potential role of these potential precursor genes may help personalize the therapy of patients with LCIS. [ABSTRACT FROM AUTHOR]

Focal extravasated mucin (EM) with benign or atypical epithelium is a rare finding at breast core needle biopsy (CNB) and usually prompts surgical excision to rule out mucin-producing carcinoma. In the largest detailed series to date, we assessed surgical outcomes in lesions yielding EM with atypical or nonatypical epithelium at CNB. With IRB approval, we retrospectively reviewed 28 consecutive atypical and nonatypical CNBs with EM that underwent surgical excision at our center over a 22-year period. CNB imaging and pathologic findings were concordant if pathology sufficiently explained the radiologic features of the lesions. Pathologic findings in CNB and excision specimens were correlated. Statistical analysis was performed. CNBs sampled mammographic calcifications in 25/28 (89%) women and a mass in 3/28 (11%). All cases had concordant pathologic and imaging findings. At CNB, the epithelium associated with EM was atypical in 18/28 (64%) lesions and nonatypical in 10 (36%). Cancer (one mucinous carcinoma; three ductal carcinoma in situ) was present in 4/28 excision specimens (14%; 95% confidence intervals [CI], 4%-33%). All carcinomas were in lesions with epithelial atypia at CNB (4/18; 22%; 95% CI, 6%-48%) versus none (0/10; 0%; 95% CI, 0%-31%) in nonatypical lesions at CNB; this difference was not statistically significant (p = 0.3). Surgery is warranted for lesions yielding EM with atypia at CNB due to the high (22%) prevalence of cancer. Our data suggest that surgical excision of lesions yielding EM without epithelial atypia at CNB may not be necessary provided that imaging and pathologic findings are concordant. [ABSTRACT FROM AUTHOR]

BACKGROUND: No consensus exists on the need to excise breast lesions that yield classic lobular carcinoma in situ (LCIS) or atypical lobular hyperplasia (ALH) (known together as classic lobular neoplasia [LN]) as the highest risk lesion at percutaneous core-needle biopsy (CNB). Here, the authors report findings from 72 consecutive lesions with LN at CNB and prospective surgical excision (EXB). METHODS: Lesions that yielded LN at CNB at the authors' center have been referred for EXB since June 2004, regardless of imaging-histologic concordance. A lesion was ' concordant' if histologic findings provided sufficient explanation for imaging. An upgrade consisted of ductal carcinoma in situ and/or invasive carcinoma at EXB. Statistical analysis, including 95% confidence intervals (CIs), was performed. RESULTS: Between June 2004 and May 2009, CNB of 85 consecutive lesions yielded LN without other high-risk histologies. Eighty of 85 lesions (94%) underwent prospective EXB. Seventy-two of 85 lesions (90%; 42 LCIS, 30 ALH) had concordant imaging-histologic findings. EXB yielded low-grade carcinoma in 2 of 72 cases (3%; 95% CI, 0%-9%). In both patients, stereotactic, 11-gauge, vacuum-assisted biopsy of calcifications yielded calcifications in benign parenchyma and ALH. CNB results were discordant in 8 of 80 lesions (10%; 4 LCIS, 4 ALH), and EXB yielded cancer in 3 of those 8 lesions (38%; 95% CI, 9%-76%). The upgrade rate was significantly higher for discordant lesions versus concordant lesions (38% vs 3%; P < .01). CONCLUSIONS: Prospective excision of LN identified carcinoma in 3% (95% CI, 0%-9%) of concordant cases versus 38% (95% CI, 9%-76%) of discordant cases. The current data provide an unbiased assessment of the upgrade rate of LN diagnosed at CNB. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: The authors evaluated the clinical characteristics, natural history, and outcomes of patients who had ≤1 cm, lymph node-negative, triple-negative breast cancer (TNBC). METHODS: After excluding patients who had received neoadjuvant therapy, 1022 patients with TNBC who underwent definitive breast surgery during 1999 to 2006 were identified from an institutional database. In total, 194 who had lymph node-negative tumors that measured ≤1 cm comprised the study population. Clinical data were abstracted, and survival outcomes were analyzed. RESULTS: The median follow-up was 73 months (range, 5-143 months). The median age at diagnosis was 55.5 years (range, 27-84 years). Tumor (T) classification was microscopic (T1mic) in 16 patients (8.2%), T1a in 49 patients (25.3%), and T1b in 129 patients (66.5%). Most tumors were poorly differentiated (n = 142; 73%), lacked lymphovascular invasion (n = 170; 87.6%), and were detected by screening (n = 134; 69%). In total, 129 patients (66.5%) underwent breast-conserving surgery, and 65 patients (33.5%) underwent mastectomy. One hundred thirteen patients (58%) received adjuvant chemotherapy, and 123 patients (63%) received whole-breast radiation. The patients who received chemotherapy had more adverse clinical and disease features (younger age, T1b tumor, poor tumor grade; all P < .05). Results from testing for the breast cancer ( BRCA) susceptibility gene were available for 49 women: 19 women had BRCA1 mutations, 7 women had BRCA2 mutations, and 23 women had no mutations. For the entire group, the 5-year local recurrence-free survival rate was 95%, and the 5-year distant metastasis-free survival rate was 95%. There was no difference between patients with T1mic/T1a tumors and patients with T1b tumors in the distant recurrence rate (94.5% vs 95.5%, respectively; P = .81) or in the receipt of chemotherapy (95.9% vs 94.5%, respectively; P = .63). CONCLUSIONS: Excellent 5-year locoregional and distant control rates were achievable in patients with TNBC who had tumors ≤1.0 cm, 58% of whom received chemotherapy. These results identified a group of patients with TNBC who had favorable outcomes after early detection and multimodality treatment. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

The aim of core needle biopsy (CNB) is to diagnose a breast abnormality prior to open surgical excision. The radiology-pathology correlation helps in interpretation of pathologic findings and is greatly assisted by specimen radiology of all cores performed for calcifications, separation of cores containing calcification from those without, and the availability of the specimen radiograph to the pathologist at the time of reporting. The nature of the imaging abnormality should also be clearly conveyed. CNB is processed in a routine manner for paraffin embedding with preservation of sufficient material in the block for further studies as needed. Possible pitfalls include the loss of calcifications at the time of section cutting, calcium remained in the formalin of the specimen container, and failure to recognize calcium oxalate deposition in the CNB. The challenges of CNB interpretation are complicated by the availability of only limited material, but are generally similar to those encountered in open surgical excision specimens. This discussion focuses on high-risk lesions and lesions that raise management issues. The most prudent approach for the pathologist is to provide sufficient information to prompt a surgical excision without overdiagnosing the lesion, thus placing the patient into the appropriate therapeutic algorithm. [ABSTRACT FROM AUTHOR]

Lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia are rare lesions, found incidentally in breast biopsies. They have been regarded traditionally as high-risk lesions, but recent genetic evidence and follow-up data indicates that they also constitute nonobligate precursors of invasive carcinoma. In addition to 16q deletion, a genetic alteration common across the spectrum of low-grade mammary epithelial neoplasia, lobular lesions consistently demonstrate deletion or functional inactivation of the CDH1/E-cadherin gene, with consequent loss of membranous immunoreactivity for the same antigen. The use of E-cadherin in the evaluation of solid mammary carcinoma in situ with ambiguous morphology has identified variants of LCIS characterized by massive acinar expansion and necrosis with calcifications, and/or marked nuclear pleomorphism or signet ring cell formation. In contrast to classic LCIS, these rare lesions are detected mammographically and often occur in association with invasive carcinoma. Genetic analysis of these tumors has confirmed lobular lineage and demonstrated more extensive chromosomal alterations than in classic LCIS. A pleomorphic variant of invasive lobular carcinoma has also been described. Here, we summarize our evolving knowledge of in situ and invasive lobular neoplasia and highlight the implications for patient management. [ABSTRACT FROM AUTHOR]

The article presents a study which found that coexisting lobular neoplasia was associated independently with a higher risk of ipsilateral breast tumor recurrence among women with ductal carcinoma in situ (DCIS) who received breast-conservation treatment. The findings suggest that women with concomitant DCIS and lobular carcinoma in situ (LCIS) may have increased risk of IBTR. It notes that concurrent lobular neoplasia maybe a phenotypic manifestation of more extensive genetic abnormalities.

The purpose of this study was to compare the ability of magnetic resonance imaging (MRI) and mammography to determine the presence and extent of ductal carcinoma in situ (DCIS). Retrospective review of medical records of women who underwent MRI and mammographic examination during a 23-month period revealed 39 sites of pure DCIS in 33 breasts of 32 women. No invasive or microinvasive tumor was found. Women ranged in age from 34 to 79 years (mean age 53 years). In these 33 breasts, both MRI and mammography were done before surgery. Reports and images of mammography and MRI were reviewed to determine if each study was positive for the presence of single or multiple sites of DCIS and the imaging patterns associated with these sites. Of 33 breasts involved, DCIS was discovered by MRI alone in 21 (64%), by both MRI and mammography in 8 (24%), and by mammography alone in 1 (3%); in 3 breasts (9%), DCIS was found at mastectomy without findings on mammography or MRI. MRI had significantly higher sensitivity than mammography for DCIS detection (29/33 = 88% versus 9/33 = 27%, p < 0.00001). Multiple sites of disease were present in five breasts; these were better demonstrated with MRI in three, mammography in one, and equally by both in one. The predominant enhancement pattern of DCIS on MRI was linear/ductal in 18 of 29 breasts (62%); mammography found calcifications associated with DCIS in 8 of 9 (89%). The nuclear grade of DCIS found with MRI and mammography was similar; size of lesions was larger on MRI; breast density did not impact results. In this study, MRI was significantly more sensitive than mammography in DCIS detection. In women with known or suspected DCIS, MRI may have an important role to play in assessing the extent of disease in the breast. [ABSTRACT FROM AUTHOR]

Aims Methods and Results Conclusion Metaplastic breast carcinoma (MBC) is a heterogeneous group of invasive breast carcinoma with squamous, spindle cell, or mesenchymal elements. It may be monophasic or biphasic, and often coexists with invasive breast carcinoma of no special type (IBC‐NST). Currently, there are no standardized guidelines for reporting MBC, and a diagnostic threshold for the metaplastic component is not established by the WHO classification.A survey conducted from April–July 2023 gathered responses from 44 pathologists worldwide. Most respondents were academic breast pathologists, and attended weekly breast tumour boards. The criteria for diagnosing MBC were highly varied, with cutoffs ranging from any/<10% to >90% metaplastic component. Although 90% was the most common threshold used, only 25% of respondents applied it. Pathologists generally preferred diagnosing invasive carcinoma with mixed features when the metaplastic component was ≤50% and MBC when the metaplastic component >50%. Most pathologists reported both the type and percentage of metaplastic component. In all, 43% reported core biopsy and resection specimen with different approaches. Diagnostic guidelines reportedly used (if any) were highly varied.The study underscores the need for standardized guidelines for MBC. Without clear and established diagnostic criteria, current data on MBC remains inconsistent and hinders further research into the clinical significance and prognostic implications of the metaplastic component. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion Breast cancer with human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) 1+ or 2+ with negative in‐situ hybridisation (ISH) (HER2‐low) can now be targeted by HER2 antibody drug conjugates. We set out to compare HER2 status between matched primary invasive breast carcinoma (IBC) and distant metastases (DM) with clinical–pathological correlation, with specific interest in HER2‐low.Biomarker studies and clinical–pathological features of primary IBC with matched DM diagnosed between 2021 and 2022 were retrospectively analysed. HER2 status was assessed per 2023 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for IHC (4B5) and ISH (IQFISH pharmDX). Bilateral breast primaries were excluded. HER2 IHC 0 to 1+ were reassessed.One hundred and forty‐seven cases of primary IBC with matched DM were identified. Biomarkers were performed on core biopsy (n = 74) and resection (n = 73). One hundred and twenty‐six (86%) were initially classified as ‘HER2‐negative’; of these, 67 (46%) were reclassified as HER2‐low. Patients with HER2‐positive primaries were younger (P = 0.01) and had an increased incidence of micropapillary carcinoma (P = 0.02). HER2‐low primaries also had an increased incidence of micropapillary carcinoma (P = 0.02) and oestrogen receptor (ER) positivity (P = 0.02) compared to HER2 0. One hundred and sixty‐nine matched DM cases excluding bone metastasis were identified (range = one to seven metastases per IBC). The most common sites of metastases were liver (50 of 169, 30%), lung (36 of 169; 21%), distant lymph node (26 of 169, 15%); 138 DM cases (82%) were previously classified as ‘HER2‐negative’, and 62 (37%) were reclassified as HER2‐low. Like HER2‐low primaries, HER2‐low metastases were frequently ER‐positive (52 of 62; 84%) (P = 0.02). Brain metastases were more frequently HER2‐positive (five of 32; 16%) (P = 0.04). Comparing HER2 status in matched primaries and DM, HER2 status was discordant in 62 cases (37%). Most changes occurred from HER2‐low to HER2 0 (33 of 169, 20%), HER2 0 to HER2‐low (17 of 169, 10%) and HER2‐low to positive (10 of 169, 6%). All HER2‐low to HER2 0 changes were HER2 1+ to 0. In 30 patients with multiple DM sites (47 cases), HER2 status among different DM samples was discordant in 16 patients (53%), mainly from HER2‐low to HER2 0 (16 of 47, 34%).A significant proportion of previous ‘HER2‐negative’ primaries and DM cases were reclassified as HER2‐low. Discordant HER2 status between IBC primary and metastasis and between different DM sites demonstrated tumour heterogeneity and highlights the need for HER2 retesting in distant metastasis. [ABSTRACT FROM AUTHOR]

Background: A 21-gene expression assay (Oncotype DX recurrence score [RS]) that uses reverse transcriptase-polymerase chain reaction is used clinically in patients with early-stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast carcinoma (ER+/HER2- BC) to determine both prognosis with tamoxifen therapy and the usefulness of adding adjuvant chemotherapy. Use of the assay is associated with reductions in overall chemotherapy use. The current study examined the treatments and outcomes in patients with low RS.Methods: The authors reviewed the institutional database to identify patients with lymph node-negative, ER+/HER2- BC who were treated at the study institution between September 2008 and August 2013 and their 21-gene RS results.Results: A total of 1406 consecutive patients with lymph node-negative ER+/HER2- BC and a low RS were identified (510 patients had an RS of 0-10 and 896 patients had an RS of 11-17). The median age at the time of diagnosis of BC was 56 years; 63 patients (4%) were aged <40 years. Overall, 1361 patients (97%) received endocrine therapy and 170 patients (12%) received chemotherapy. The median follow-up was 46 months. Six patients (0.4%) developed distant metastases (1 patient with an RS of 5 and 5 patients with an RS of 11-17). In the cohorts of patients with an RS of 11 to 17, the absolute rate of distant metastasis among patients aged <40 years was 7.1% (3 of 42 patients) versus 0.2% among patients aged ≥40 years (2 of 854 patients).Conclusions: The data from the current study document a 0.4% rate of distant metastasis within 5 years of BC diagnosis among patients with lymph node-negative ER+/HER2- BC with an RS <18. Patients aged <40 years at the time of BC diagnosis were observed to have a higher rate of distant metastases. Analysis of data from other studies is necessary to validate this observation further. Cancer 2017;131-137. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]