Author Correction: Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

In the Methods section of this Article, 'greater than' should have been 'less than' in the sentence 'Putative regions of clustered rearrangements were identified as having an average inter-rearrangement distance that was at least 10 times greater than the whole-genome average for the individual sample. '. The Article has not been corrected.

TBCRC 039: a phase II study of preoperative ruxolitinib with or without paclitaxel for triple-negative inflammatory breast cancer.

BACKGROUND: Patients with inflammatory breast cancer (IBC) have overall poor clinical outcomes, with triple-negative IBC (TN-IBC) being associated with the worst survival, warranting the investigation of novel therapies. Preclinical studies implied that ruxolitinib (RUX), a JAK1/2 inhibitor, may be an effective therapy for TN-IBC. METHODS: We conducted a randomized phase II study with nested window-of-opportunity in TN-IBC. Treatment-naïve patients received a 7-day run-in of RUX alone or RUX plus paclitaxel (PAC). After the run-in, those who received RUX alone proceeded to neoadjuvant therapy with either RUX + PAC or PAC alone for 12 weeks; those who had received RUX + PAC continued treatment for 12 weeks. All patients subsequently received 4 cycles of doxorubicin plus cyclophosphamide prior to surgery. Research tumor biopsies were performed at baseline (pre-run-in) and after run-in therapy. Tumors were evaluated for phosphorylated STAT3 (pSTAT3) by immunostaining, and a subset was also analyzed by RNA-seq. The primary endpoint was the percent of pSTAT3-positive pre-run-in tumors that became pSTAT3-negative. Secondary endpoints included pathologic complete response (pCR). RESULTS: Overall, 23 patients were enrolled, of whom 21 completed preoperative therapy. Two patients achieved pCR (8.7%). pSTAT3 and IL-6/JAK/STAT3 signaling decreased in post-run-in biopsies of RUX-treated samples, while sustained treatment with RUX + PAC upregulated IL-6/JAK/STAT3 signaling compared to RUX alone. Both treatments decreased GZMB+ T cells implying immune suppression. RUX alone effectively inhibited JAK/STAT3 signaling but its combination with PAC led to incomplete inhibition. The immune suppressive effects of RUX alone and in combination may negate its growth inhibitory effects on cancer cells. CONCLUSION: In summary, the use of RUX in TN-IBC was associated with a decrease in pSTAT3 levels despite lack of clinical benefit. Cancer cell-specific-targeting of JAK2/STAT3 or combinations with immunotherapy may be required for further evaluation of JAK2/STAT3 signaling as a cancer therapeutic target. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , NCT02876302. Registered 23 August 2016.

A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis.

MicroRNAs are well suited to regulate tumor metastasis because of their capacity to coordinately repress numerous target genes, thereby potentially enabling their intervention at multiple steps of the invasion-metastasis cascade. We identify a microRNA exemplifying these attributes, miR-31, whose expression correlates inversely with metastasis in human breast cancer patients. Overexpression of miR-31 in otherwise-aggressive breast tumor cells suppresses metastasis. We deploy a stable microRNA sponge strategy to inhibit miR-31 in vivo; this allows otherwise-nonaggressive breast cancer cells to metastasize. These phenotypes do not involve confounding influences on primary tumor development and are specifically attributable to miR-31-mediated inhibition of several steps of metastasis, including local invasion, extravasation or initial survival at a distant site, and metastatic colonization. Such pleiotropy is achieved via coordinate repression of a cohort of metastasis-promoting genes, including RhoA. Indeed, RhoA re-expression partially reverses miR-31-imposed metastasis suppression. These findings indicate that miR-31 uses multiple mechanisms to oppose metastasis.

Landscape of somatic mutations in 560 breast cancer whole-genome sequences.

We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.

Can pathology diagnostic services for cancer be stratified and serve global health?

BACKGROUND: Before initiating cancer therapy, a diagnostic tumor tissue sample evaluated within a pathology laboratory by a pathologist is essential to confirm the malignancy type and provide key prognostic factors that direct the treatment offered. METHODS: Pathology evaluation includes multiple expensive reagents, complex equipment, and both laboratory and pathologist technical skills. By using breast cancer as an example, at a minimum, key tumor prognostic information required before the initiation of treatment includes subtype, tumor grade, tumor size, lymph node status when possible, and biomarker expression determined by immunohistochemistry for estrogen receptor. The additional determination of biomarker expression of progesterone receptor and human epidermal growth factor receptor (HER2) is the standard of care in high-resource settings, but assays may not be affordable in low-income and middle-income countries. RESULTS: With positive tests, patients are eligible for either tamoxifen (for estrogen receptor-positive/progesterone receptor-positive cancers) or monoclonal antibody therapy (for HER2-positive cancers). For settings in which endocrine therapy and/or HER2-targeted therapy is unavailable, biomarker studies have no utility, and high-resource setting standards for pathology evaluation and reporting are unachievable. Resource-stratified pathology evaluation guidelines in cancer diagnosis have not been developed, in contrast to excellent comprehensive, resource-stratified clinical guidelines for use in low-income and middle-income countries, and these are long overdue. CONCLUSIONS: The challenges of pathology evaluation in the context of global health are being met by innovative solutions, which may change the face of pathology practice.

Safety-Net Hospitals, Neighborhood Disadvantage, and Readmissions Under Maryland's All-Payer Program: An Observational Study.

Background: Safety-net hospitals have higher-than-expected readmission rates. The relative roles of the mean disadvantage of neighborhoods the hospitals serve and the disadvantage of individual patients in predicting a patient's readmission are unclear. Objective: To examine the independent contributions of the patient's neighborhood and the hospital's service area to risk for 30-day readmission. Design: Retrospective observational study. Setting: Maryland. Participants: All Maryland residents discharged from a Maryland hospital in 2015. Measurements: Predictors included the disadvantage of neighborhoods for each Maryland resident (area disadvantage index) and the mean disadvantage of each hospital's discharged patients (safety-net index). The primary outcome was unplanned 30-day hospital readmission. Generalized estimating equations and marginal modeling were used to estimate readmission rates. Results were adjusted for clinical readmission risk. Results: 13.4% of discharged patients were readmitted within 30 days. Patients living in neighborhoods at the 90th percentile of disadvantage had a readmission rate of 14.1% (95% CI, 13.6% to 14.5%) compared with 12.5% (CI, 11.8% to 13.2%) for similar patients living in neighborhoods at the 10th percentile. Patients discharged from hospitals at the 90th percentile of safety-net status had a readmission rate of 14.8% (CI, 13.4% to 16.1%) compared with 11.6% (CI, 10.5% to 12.7%) for similar patients discharged from hospitals at the 10th percentile of safety-net status. The association of readmission risk with the hospital's safety-net index was approximately twice the observed association with the patient's neighborhood disadvantage status. Limitations: Generalizability outside Maryland is unknown. Confounding may be present. Conclusion: In Maryland, residing in a disadvantaged neighborhood and being discharged from a hospital serving a large proportion of disadvantaged neighborhoods are independently associated with increased risk for readmission. Primary Funding Source: National Institute on Minority Health and Health Disparities and Maryland Health Services Cost Review Commission.

Impact of Genomic Assay Testing and Clinical Factors on Chemotherapy Use After Implementation of Standardized Testing Criteria.

BACKGROUND: For clinically appropriate early-stage breast cancer patients, reflex criteria for Oncotype DX ordering ("the intervention") were implemented at our comprehensive cancer center, which reduced time-to-adjuvant chemotherapy initiation. Our objective was to evaluate Oncotype DX ordering practices and chemotherapy use before and after implementation of the intervention. MATERIALS AND METHODS: We examined medical records for 498 patients who had definitive breast cancer surgery at our center. The post-intervention cohort consisted of 232 consecutive patients who had Oncotype DX testing after reflex criteria implementation. This group was compared to a retrospective cohort of 266 patients who were diagnosed and treated prior to reflex criteria implementation, including patients who did and did not have Oncotype DX ordered. Factors associated with Oncotype DX ordering pre- and post-intervention were examined. We used multivariate logistic regression to evaluate factors associated with chemotherapy receipt among patients with Oncotype DX testing. RESULTS: The distribution of Oncotype DX scores, the proportion of those having Oncotype DX testing (28.9% vs. 34.1%) and those receiving chemotherapy (14.3% vs. 19.4%), did not significantly change between pre- and post-intervention groups. Age ≤65 years, stage II, grade 2, 1-3+ nodes, and tumor size >2 cm were associated with higher odds of Oncotype DX testing. Among patients having Oncotype DX testing, node status and Oncotype DX scores were significantly associated with chemotherapy receipt. CONCLUSION: Our criteria for reflex Oncotype DX ordering appropriately targeted patients for whom Oncotype DX would typically be ordered by providers. No significant change in the rate of Oncotype DX ordering or chemotherapy use was observed after reflex testing implementation. IMPLICATIONS FOR PRACTICE: This study demonstrates that implementing multidisciplinary consensus reflex criteria for Oncotype DX ordering maintains a stable Oncotype DX ordering rate and chemotherapy rate, mirroring what was observed in a specific clinical practice, while decreasing treatment delays due to additional testing. These reflex criteria appropriately capture patients who would likely have had Oncotype DX ordered by their providers and for whom the test results are predicted to influence management. This intervention serves as a potential model for other large integrated, multidisciplinary oncology centers to institute processes targeting patient populations most likely to benefit from genomic assay testing, while mitigating treatment delays.

Mixed Invasive Ductal and Lobular Carcinoma of the Breast: Prognosis and the Importance of Histologic Grade.

BACKGROUND: The diagnosis of mixed invasive ductal and lobular carcinoma (IDC-L) in clinical practice is often associated with uncertainty related to its prognosis and response to systemic therapies. With the increasing recognition of invasive lobular carcinoma (ILC) as a distinct disease subtype, questions surrounding IDC-L become even more relevant. In this study, we took advantage of a detailed clinical database to compare IDC-L and ILC regarding clinicopathologic and treatment characteristics, prognostic power of histologic grade, and survival outcomes. MATERIALS AND METHODS: In this retrospective cohort study, we identified 811 patients diagnosed with early-stage breast cancer with IDC-L or ILC. Descriptive statistics were performed to compare baseline clinicopathologic characteristics and treatments. Survival rates were subsequently analyzed using the Kaplan-Meier method and compared using the Cox proportional hazards model. RESULTS: Patients with ILC had more commonly multifocal disease, low to intermediate histologic grade, and HER2-negative disease. Histologic grade was prognostic for patients with IDC-L but had no significant discriminatory power in patients with ILC. Among postmenopausal women, those with IDC-L had significantly better outcomes when compared with those with ILC: disease-free survival (DFS) and overall survival (OS; adjusted hazard ratio [HR], 0.54; 95% confidence interval [CI] 0.31-0.95). Finally, postmenopausal women treated with an aromatase inhibitor had more favorable DFS and OS than those treated with tamoxifen only (OS adjusted HR, 0.50; 95% CI, 0.29-0.87), which was similar for both histologic types (p = .212). CONCLUSION: IDC-L tumors have a better prognosis than ILC tumors, particularly among postmenopausal women. Histologic grade is an important prognostic factor in IDC-L but not in ILC. IMPLICATIONS FOR PRACTICE: This study compared mixed invasive ductal and lobular carcinoma (IDC-L) with invasive lobular carcinomas (ILCs) to assess the overall prognosis, the prognostic role of histologic grade, and response to systemic therapy. It was found that patients with IDC-L tumors have a better prognosis than ILC, particularly among postmenopausal women, which may impact follow-up strategies. Moreover, although histologic grade failed to stratify the risk of ILC, it showed an important prognostic power in IDC-L, thus highlighting its clinical utility to guide treatment decisions of IDC-L. Finally, the disease-free survival advantage of adjuvant aromatase inhibitors over tamoxifen in ILC was consistent in IDC-L.

Long-term outcomes of breast-conserving therapy for women with ductal carcinoma in situ.

PURPOSE: Improved imaging, surgical techniques, and pathologic evaluation likely have decreased local recurrence rates for patients with ductal carcinoma in situ (DCIS). We present long-term outcomes of a large single-institution series after breast-conserving surgery (BCS) and adjuvant radiation therapy (RT). METHODS: We retrospectively reviewed the records of 245 women treated for DCIS with BCS and RT between 2001 and 2007. Competing risk analysis was used to calculate local recurrence (LR) as a first event with the development of a second non-breast malignancy, contralateral breast cancer, and death as competing first events. RESULTS: At a median follow-up of 10.6 years, 4 patients had a LR (2 DCIS, 2 invasive) as a first event with a cumulative LR incidence of 0.0% and 1.5% at 5 and 10 years, respectively. Most patients had > 2 mm margins (90%), specimen radiographs (93%), and received a tumor bed boost (99%). The majority (60%) of patients with hormone receptor-positive disease received adjuvant endocrine therapy. Ten-year cumulative incidence of contralateral breast cancer (CBC) was 7.9%, second non-breast malignancy was 4.5%, and death unrelated to breast cancer was 3.5%. Family history, age at diagnosis, and receipt of endocrine therapy were not significantly associated with the development of CBC (all P > 0.05). CONCLUSIONS: With mature follow-up, our rates of local recurrence following breast-conserving therapy for DCIS remain very low (1.5% at 10 years). The incidence of CBC was higher than the LR incidence. Predisposing factors for the development of CBC are worthy of investigation.

Distinguishing papillary endothelial hyperplasia and angiosarcoma on core needle biopsy of the breast: The importance of clinical and radiologic correlation.

Papillary endothelial hyperplasia (PEH) is a rare non-neoplastic exuberant organizing hematoma that can closely mimic angiosarcoma due to a resemblance to malignant anastomosing blood vessels. It could be particularly difficult to distinguish PEH from angiosarcoma in breast core needle biopsies. We identified all cases of these lesions diagnosed on core needle biopsy in order to identify clinical, radiologic, and pathologic features that could prove helpful to arrive at the correct diagnosis. Four cases of PEH and 4 cases of angiosarcoma were identified. The mean age at diagnosis was 62 for PEH and 33 for primary angiosarcoma. All cases of PEH formed small masses with circumscribed or lobulated margins by imaging (mean size 0.9 cm). In 3 cases, the masses were difficult or impossible to identify after the biopsy. Angiosarcomas presented as larger masses with ill-defined margins (mean size 2.8 cm) that were unchanged in size after biopsy. PEH was surrounded by adipose tissue, whereas angiosarcoma invaded into fibrous stroma and involved lobules. The pseudopapillary structures of PEH were composed mainly of collagen, and thus, additional histologic stains for fibrin were not helpful for diagnosis. The 4 patients with PEH received no further treatment and are alive and disease-free at 2-11 years of follow-up. In contrast, the patients with angiosarcoma underwent mastectomy and chemotherapy or radiation therapy. Two of the patients with angiosarcoma died 3 years after diagnosis and the other 2 patients are alive without disease at 5 and 6 years. Therefore, distinguishing PEH and angiosarcoma is essential for appropriate management. This is the first series to compare these lesions on core needle biopsy and the first to note important clinical, imaging, and histologic differences that aid in making a diagnosis of PEH with confidence on breast core needle biopsy.

Estimated Cost Savings: Everyone With Diabetes Counts (EDC) Program.

Everyone with Diabetes Counts (EDC) is a national disparities reduction program funded by the Centers for Medicare & Medicaid Services to improve outcomes in the underserved minority, diverse, and rural populations. This analysis evaluates West Virginia's pilot program of diabetes self-management education (DSME), one component of EDC. We frequency-matched 422 DSME completers to 1688 others by demographics and enrollment from Medicare fee-for service claims. We estimated savings associated with reduced hospitalizations in multivariable negative binomial models. DSME completers had 29% fewer hospitalizations (adjusted P < .0069). We estimated savings of $35 900 per 100 DSME completers in West Virginia.

Phase II and Biomarker Study of Cabozantinib in Metastatic Triple-Negative Breast Cancer Patients.

Currently, no targeted therapies are available for metastatic triplenegative breast cancer (mTNBC). We evaluated the safety, efficacy, and biomarkers of response to cabozantinib, a multikinase inhibitor, in patients with mTNBC. We conducted a single arm phase II and biomarker study that enrolled patients with measurable mTNBC. Patients received cabozantinib (60 mg daily) on a 3-week cycle and were restaged after 6 weeks and then every 9 weeks. The primary endpoint was objective response rate. Predefined secondary endpoints included progression-free survival (PFS), toxicity, and tissue and blood circulating cell and protein biomarkers. Of 35 patients who initiated protocol therapy, 3 (9% [95% confidence interval (CI): 2, 26]) achieved a partial response (PR). Nine patients achieved stable disease (SD) for at least 15 weeks, and thus the clinical benefit rate (PR+SD) was 34% [95% CI: 19, 52]. Median PFS was 2.0 months [95% CI: 1.3, 3.3]. The most common toxicities were fatigue, diarrhea, mucositis, and palmar-plantar erythrodysesthesia. There were no grade 4 toxicities, but 12 patients (34%) required dose reduction. Two patients had TNBCs with MET amplification. During cabozantinib therapy, there were significant and durable increases in plasma placental growth factor, vascular endothelial growth factor (VEGF), VEGF-D, stromal cell-derived factor 1a, and carbonic anhydrase IX, and circulating CD3 + cells and CD8 + T lymphocytes, and decreases in plasma soluble VEGF receptor 2 and CD14+ monocytes (all p < .05). Higher baseline concentrations of soluble MET (sMET) associated with longer PFS (p = .03). In conclusion, cabozantinib showed encouraging safety and efficacy signals but did not meet the primary endpoint in pretreated mTNBC. Exploratory analyses of circulating biomarkers showed that cabozantinib induces systemic changes consistent with activation of the immune system and antiangiogenic activity, and that sMET should be further evaluated a potential biomarker of response. IMPLICATIONS FOR PRACTICE: Triple-negative breast cancer (TNBC)-a disease with a dearth of effective therapies-often overexpress MET, which is associated with poor clinical outcomes. However, clinical studies of agents targeting MET and VEGF pathways-alone or in combination-have shown disappointing results. This study of cabozantinib (a dual VEGFR2/MET) in metastatic TNBC, while not meeting its prespecified endpoint, showed that treatment is associated with circulating biomarker changes, and is active in a subset of patients. Furthermore, this study demonstrates that cabozantinib therapy induces a systemic increase in cytotoxic lymphocyte populations and a decrease in immunosuppressive myeloid populations. This supports the testing of combinations of cabozantinib with immunotherapy in future studies in breast cancer patients.

Benign and Malignant Breast Disease at Rwanda's First Public Cancer Referral Center.

BACKGROUND: Breast cancer incidence is rising in low- and middle-income countries. Understanding the distribution of breast disease seen in clinical practice in such settings can guide early detection efforts and clinical algorithms, as well as support future monitoring of cancer detection rates and stage. PATIENTS AND METHODS: We conducted a retrospective medical record review of 353 patients who presented to Butaro Cancer Center of Excellence in Rwanda with an undiagnosed breast concern during the first 18 months of the cancer program. RESULTS: Eighty-two percent of patients presented with a breast mass. Of these, 55% were diagnosed with breast cancer and 36% were diagnosed with benign disease. Cancer rates were highest among women 50 years and older. Among all patients diagnosed with breast cancer, 20% had stage I or II disease at diagnosis, 46% had locally advanced (stage III) disease, and 31% had metastatic disease. CONCLUSION: After the launch of Rwanda's first public cancer referral center and breast clinic, cancer detection rates were high among patients presenting with an undiagnosed breast concern. These findings will provide initial data to allow monitoring of changes in the distribution of benign and malignant disease and of cancer stage as cancer awareness and services expand nationally. IMPLICATIONS FOR PRACTICE: The numbers of cases and deaths from breast cancer are rising in low-income countries. In many of these settings, health care systems to address breast problems and efficiently refer patients with symptoms concerning for cancer are rudimentary. Understanding the distribution of breast disease seen in such settings can guide early detection efforts and clinical algorithms. This study describes the characteristics of patients who came with a breast concern to Rwanda's first public cancer referral center during its first 18 months. More than half of patients with a breast mass were diagnosed with cancer; most had late-stage disease. Monitoring changes in the types of breast disease and cancer stages seen in Rwanda will be critical as breast cancer awareness and services grow.

Invasive lobular carcinoma of the breast: local recurrence after breast-conserving therapy by subtype approximation and surgical margin.

Invasive lobular carcinoma (ILC) typically presents at a later stage than invasive ductal carcinoma (IDC) and poses unique radiographic and surgical challenges. However, current principles of breast-conserving therapy (BCT) do not distinguish between histologic subtypes, raising uncertainty about the optimal approach for patients with ILC. We studied 998 BCT patients from 1998-2007, comprised 74 % IDC, 8 % ILC, and 18 % with mixed ILC/IDC. In light of recent guidelines addressing surgical margins, specimens were assessed for margin width and biologic subtype. The Kaplan-Meier method and Cox proportional hazards models were used to analyze effects of patient and disease characteristics on local recurrence (LR). At a median of 119 months, 45 patients had an isolated LR. 10-year LR was 5.5 % for patients with IDC, 4.4 % for ILC, and 1.2 % for mixed histology (p = 0.08). The majority of ILC cases had luminal A biologic subtype (91.1 %), and analysis among all luminal A cases revealed 10-year LR of 2.6 % for IDC, 3.4 % for ILC, and 0 % for mixed tumors (p = 0.12). Patients with ILC were more likely to have initially positive surgical margins (45.0 vs 17.5 %; p < 0.001) resulting in more frequent re-excision (57.1 % vs 40.4 %; p = 0.02), though final margins were similar between ILC and IDC (p = 0.88). No LR was observed among ILC or mixed histology patients with margins <2 mm (n = 28). On multivariate analysis, histologic subtype was not associated with LR (p = 0.52). Modern approaches confer similarly favorable LR rates for ILC, IDC, and mixed histology breast cancers despite inherent histologic differences. Patients with ILC did not require more extensive surgical margins than those with IDC.

Modern Trends in the Surgical Management of Paget's Disease.

PURPOSE: We examined the incidence and modern national trends in the management of Paget's disease (PD), including the use of breast-conserving surgery (BCS), mastectomy, axillary surgery, and receipt of radiotherapy. METHODS: Using surveillance, epidemiology and end results (SEER) data, we identified 2631 patients diagnosed with PD during 2000-2011. Of these patients, 185 (7%) had PD of the nipple only, 953 (36.2%) had PD with ductal carcinoma in situ (PD-DCIS), and 1493 (56.7%) had PD with invasive ductal carcinoma (PD-IDC). Trends in age-adjusted incidence, primary surgery, sentinel lymph node biopsy (SLNB), and axillary lymph node dissection were examined. Multivariable logistic regression was used to evaluate factors associated with receipt of BCS and radiotherapy. RESULTS: A decrease in the age-adjusted incidence of PD occurred from 2000 to 2011 (-4.3% per year, p < 0.05). The overall rates of mastectomy in the PD only, PD-DCIS, and PD-IDC groups were 47, 69, and 88.9%, respectively. Only in the PD-IDC group did the proportion of patients undergoing BCS increase significantly, from 8.5% in 2000 to 15.7% in 2011 (p = 0.01). Of those who underwent axillary surgery, the proportion of patients undergoing SLNB increased from 2000 to 2011. In adjusted analyses, Paget's subgroup, older age, central tumor location, low/intermediate grade, tumor size <2.0 cm, SEER region, and year of diagnosis after 2006 were significantly associated with receipt of BCS. CONCLUSIONS: The incidence of Paget's disease has decreased over time while modern trends in local therapy suggest that BCS, SLNB, and adjuvant radiotherapy remain underutilized.

Surgical Options and Locoregional Recurrence in Patients Diagnosed with Invasive Lobular Carcinoma of the Breast.

PURPOSE: Recent consensus guidelines on margins for breast-conserving surgery (BCS) recommend the use of "no ink on tumor" as the standard for an adequate margin. The recommendations extend to invasive lobular carcinoma (ILC), but the data on this subset are limited. We reviewed our modern dataset on margin status with outcomes of ILC. METHODS: We performed a retrospective cohort study on 736 patients with a diagnosis of stage I-III ILC treated at our cancer center between May 1997 and December 2007. Clinicopathologic data were extracted from the Clinical Research Information Systems Database. Margin status was defined using the latest ASCO/ASTRO/SSO consensus guideline criteria. RESULTS: The initial surgery performed was mastectomy in 352 patients (48 %) and BCS in 384 patients (52 %). In multivariate analysis, tumor size and multifocality were significantly associated with high rates of mastectomy and positive surgical margins at initial BCS. After initial BCS, additional surgery was performed in 92 patients (24 %). During a 72-month median follow-up period, 12 (3.1 %) ipsilateral breast tumor recurrences (IBTR) and 5 (1.3 %) other locoregional recurrences (LRR) were observed. Patients with margins with ink on tumor who did not receive further surgery were found to have significantly increased LRR [odds ratio (OR) 5.5; p = 0.02] and IBTR (OR 8.5; p = 0.006), whereas patients with close margins (1-3 mm) and margins within 1 mm were not. CONCLUSIONS: Our study supports the validity of using "no ink on tumor" as the standard for a negative margin for pure and mixed ILC treated with multimodality therapy.

MRI-guided breast needle core biopsies: pathologic features of newly diagnosed malignancies.

Magnetic resonance imaging (MRI) of the breast is used for select groups of patients. MRI-guided breast core needle biopsies performed over a 3-year period were retrospectively reviewed to determine the incidence and types of cancers found and to correlate the cancers with the MRI findings and the indication for the study. Patients were stratified based on indication for MRI examination including, evaluation of disease extent in patients with current ipsilateral carcinoma, surveillance for recurrence of prior ipsilateral carcinoma, as a problem-solving method and for screening high-risk patients. The high-risk screening group included those with family history (with or without germline mutations), prior chest wall radiation, and contralateral breast carcinoma (current or prior). Four-hundred and forty-five biopsies were performed on 386 patients. The majority of biopsies (79%) were benign. Biopsies demonstrating ductal carcinoma in situ (DCIS) and invasive carcinoma were more likely to present as nonmass-like and mass-forming enhancements respectively, but with only 52% specificity. The highest rate of malignancy (44%) was seen in the least frequently biopsied patient group (n = 25), those with prior ipsilateral carcinoma. Conversely, the most frequently biopsied group (n = 283), the high-risk screening group, demonstrated the lowest malignancy rate (16%). Within this group, most malignant cases were invasive carcinomas (n = 27), 67% of which were small (≤1 cm), well or moderately differentiated with a good prognostic receptor profile (estrogen receptor positive, human epidermal growth factor receptor 2 negative), and lacked nodal macrometastases. The remaining malignant cases in the high-risk screening group were DCIS with or without microinvasion (n = 18), 78% of which demonstrated high nuclear grade. Overall, enhancement pattern did not correlate with the likelihood of or type of malignancy. The most common types of carcinomas identified by screening were small estrogen receptor positive invasive tumors and high grade DCIS.

Non-sclerosing (T-cell) and sclerosing (B-cell) lymphocytic lobulitis in diagnostic breast biopsies: Clinical, imaging, and pathologic features.

Lymphocytic lobulitis (LL) is characterized by prominent lymphocytic infiltrates centered on lobules. Sclerosing lymphocytic lobulitis (SCLL) associated with diabetes mellitus (DM) or autoimmune disease (AI) was the first type to be described. Subsequently, non-sclerosing LL (NSCLL) was reported as an incidental finding in prophylactic mastectomies due to high risk germline mutations or a family history of breast cancer. The two types of LL were distinguished by stromal features and a predominant population of B-cells in the former and T-cells in the latter. In this study, 8 cases of NSCLL detected clinically or by screening were compared to 44 cases of SCLL. One case of NSCLL presented as a palpable mass, 2 as masses on screening, and 5 as MRI enhancement. In contrast, 80% of SCLL cases presented as palpable masses. Half the cases of NSCLL were associated with a BRCA1 or 2 mutation compared to 1 case of SCLL (2%). Three additional cases of NSCLL were associated with a strong family and/or personal history of breast cancer. Almost half (52%) of SCLL cases were associated with DM or AI, but only 25% of NSCLL. Immunoperoxidase studies confirmed a predominance of T-cells in NSCLL and B-cells in SCLL associated with DM or AI. It is important for pathologists to be aware of this new observation that NSCLL can be detected as a palpable mass or an imaging finding in diagnostic biopsies, as its presence can be indicative of a significant risk for breast cancer.

Margin status and the risk of local recurrence in patients with early-stage breast cancer treated with breast-conserving therapy.

We sought to assess whether a close surgical margin (>0 and <2 mm) after breast-conserving therapy (BCT) confers an increased risk of local recurrence (LR) compared with a widely negative margin (≥2 mm). We studied 906 women with early-stage invasive breast cancer treated with BCT between January 1998 and October 2006; 91 % received adjuvant systemic therapy. Margins were coded as: (1) widely negative (n = 729), (2) close (n = 85), or (3) close (n = 84)/positive (n = 8) but having no additional tissue to remove according to the surgeon. Cumulative incidence of LR and distant failure (DF) were calculated using the Kaplan-Meier method. Gray's competing-risk regression assessed the effect of margin status on LR and Cox proportional hazards regression assessed the effect on DF, controlling for biologic subtype, age, and number of positive lymph nodes (LNs). Three hundred seventy-seven patients (41.6 %) underwent surgical re-excision, of which 63.5 % had no residual disease. With a median follow-up of 87.5 months, the 5-year cumulative incidence of LR was 2.5 %. The 5-year cumulative incidence of LR by margin status was 2.3 % (95 % CI 1.4-3.8 %) for widely negative, 0 % for close, and 6.4 % (95 % CI 2.7-14.6 %) for no additional tissue, p = 0.3. On multivariate analysis, margin status was not associated with LR; however, triple-negative subtype (AHR 3.7; 95 % CI 1.6-8.8; p = 0.003) and increasing number of positive LNs (AHR 1.6; 95 % CI 1.1-2.3; p = 0.025) were associated. In an era of routine adjuvant systemic therapy, close surgical margins and maximally resected close/positive margins were not associated with an increased risk of LR compared to widely negative margins. Additional studies are needed to confirm this finding.