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Objectives Trastuzumab (H) and pertuzumab (P) with standard chemotherapy is approved for use in the neoadjuvant setting for human epidermal growth receptor 2 -positive patients. A retrospective analysis was performed of patients treated with dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T), trastuzumab, and pertuzumab (THP) in the neoadjuvant setting. Here, the pathologic complete response (pCR) rates are reported. Methods An electronic medical record review was conducted of patients treated with HP-based therapy in the neoadjuvant setting from September 1, 2013, to March 1, 2015. Data on patient demographics, stage of breast cancer, pathology reports, surgical data, and information on systemic therapy were collected. The pCR was defined as total (tpCR, ypT0/is ypN0), German Breast Group (GBG) pCR (ypT0 ypN0), breast pCR (bpCR) with in situ disease (ypT0/is) and without in situ disease (ypT0), and explored axillary pCR (ypN0). Results Charts from 66 patients were reviewed, and 57 patients were evaluable for pCR. Median age was 46 years (range 26-68 years). Median tumor size was 4 cm. Of 57 patients, 53 (93%) had operable breast cancer (T1-3, N0-1, M0). Three patients (5.3%) had locally advanced disease (T2-3, N2-3, M0 or T4a-c, any N, M0), and 1 (1.7%) had inflammatory breast cancer (T4d, any N, M0). Overall, 44 (77%) and 13 (23%) had hormone receptor (HR)-positive and negative diseases, respectively. Median numbers of cycles of neoadjuvant treatment were as follows: AC (4, range 1-4), T (4, range 1-4), trastuzumab (6, range 3-8), and pertuzumab (6, range 2-8). In these 57 patients, the rates of tpCR and bpCR with in situ disease were demonstrated in 41/57 (72%) patients, and the rates of GBG pCR and bpCR without in situ disease were found in 30/57 (53%) patients. Of 26 patients with biopsy-proven lymph nodal involvement, axillary pCR occurred in 22 (85%) patients. Conclusion At a single center, the tpCR and GBG pCR rates of dd AC followed by THP are high at 72% and 53%, respectively. The Oncologist 2017;22:139-143Implications for Practice: This is the first study describing the role of doxorubicin and cyclophosphamide followed by paclitaxel and dual anti-HER2 therapy with trastuzumab and pertuzumab (ACTHP) in patients with early stage HER2-positive breast cancer. Total (breast + lymph node) pathological complete remission (pCR) remission (ypT0/is ypN0) and German Breast Group pCR rates (ypT0/ ypN0) were high at 72% and 53%, respectively, with the ACTHP regimen. Rate of axillary clearance in patients with known axillary involvement was high at 85%, which may translate into less extensive axillary surgeries in this subset in the future.

The phrase “high-risk for breast cancer” is used to identify various groups at elevated cancer risk, and the appropriate surveillance and risk-reducing strategies differ based on the etiology of risk. Here, we review the utility of patient-reported data to capture women with modifiable lifestyle risk factors and those suitable for genetic counseling referral. Patient-reported data from a web-based survey were used to capture personal history, multi-generational family history, and lifestyle factors (body mass index, alcohol consumption, physical activity). Responses were tabulated, and percentage of patients who met criteria for possible intervention calculated. 1277 women completed the survey from October 2014 to December 2015. Women were considered high risk for a combination of the following: family history of breast and/or ovarian cancer (77%), history of atypical hyperplasia or lobular carcinoma in situ (35%), known breast cancer-related gene mutation (11%). Based on self-reported data, 65% qualified for genetic evaluation but 40% reporting no prior testing. Only half of the population met national physical activity recommendations, nearly 40% were overweight/obese, and 18% reported consuming ≥1 alcoholic beverage per day. Among women followed in a high-risk breast surveillance program, there is considerable opportunity for improved genetic referral and awareness of modifiable lifestyle factors based on self-reported data as 60% of respondents reported a possible area for intervention. While risk reduction associated with lifestyle changes is modest in comparison to chemoprevention or surgery, such changes are practically without risk, minimally expensive, and provide innumerable secondary health benefits.

BACKGROUND Patient-reported toxicities help to appraise the breast cancer treatment experience. Yet extant data come from clinical trials and health care claims, which may be biased. Using patient surveys, the authors sought to quantify the frequency, severity, and burden of treatment-associated toxicities. METHODS Between 2013 and 2014, the iCanCare study surveyed a population-based sample of women residing in Los Angeles County and Georgia with early-stage, invasive breast cancer. The authors assessed the frequency and severity of toxicities; correlated toxicity severity with unscheduled health care use (clinic visits, emergency department visits/hospitalizations) and physical health; and examined patient, tumor, and treatment factors associated with reporting increased toxicity severity. RESULTS The overall survey response rate was 71%. From the analyzed cohort of 1945 women, 866 (45%) reported at least 1 toxicity that was severe/very severe, 9% reported unscheduled clinic visits for toxicity management, and 5% visited an emergency department or hospital. Factors associated with reporting higher toxicity severity included receipt of chemotherapy (odds ratio [OR], 2.2; 95% confidence interval [95% CI], 2.0-2.5), receipt of both chemotherapy and radiotherapy (OR, 1.3; 95% CI, 1.0-1.7), and Latina ethnicity (OR vs whites: 1.3; 95% CI, 1.1-1.5). A nonsignificant increase in at least 1 severe/very severe toxicity report was observed for bilateral mastectomy recipients (OR, 1.2; 95% CI, 1.0-1.4). CONCLUSIONS Women with early-stage invasive breast cancer report substantial treatment-associated toxicities and related burden. Clinicians should collect toxicity data routinely and offer early intervention. Toxicity differences observed by treatment modality may inform decision making. Cancer 2017;123:1925–1934. © 2017 American Cancer Society.

This study aimed to determine the relationship between mammographic calcifications and magnetic resonance imaging (MRI) tumoral enhancement before and after neoadjuvant chemotherapy (NAC) and to assess the impact of these findings on surgical management. This Institutional Review Board-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective study involved breast cancer patients who underwent NAC between 2009 and 2015. The study cohort comprised 90 patients with pre- and posttreatment MRI and mammograms demonstrating calcifications within the tumor bed either at presentation or after treatment. The data gathered included pre- and post-NAC imaging findings and post-NAC histopathology, particularly findings associated with calcifications. Comparisons were made using Fisher’s exact test, with p values lower than 0.05 considered significant. Complete resolution of MRI enhancement occurred for 44% of the patients, and a pathologic complete response (pCR) was achieved for 32% of the patients. No statistically significant correlation between changes in mammographic calcifications and MRI enhancement was found (p = 0.12). Resolution of enhancement was strongly correlated with pCR (p < 0.0001). The majority of the patients with pCR demonstrated complete resolution of enhancement (79%, 23/29). No statistically significant relationship was found between changes in calcifications and rates of pCR (p = 0.06). A pCR was achieved most frequently for patients with resolution of enhancement and new, increasing, or unchanged calcifications (p < 0.0001). Although calcifications seen on post-NAC mammography may be associated with benign disease, loss of MRI enhancement does not predict the absence of residual tumor with sufficient accuracy to leave calcifications in place. Complete excision of tumor bed calcifications remains standard practice and a substantial limitation to NAC use for downstaging patients to be eligible for breast conservation treatment.

The American Society of Clinical Oncology/College of American Pathologists HER2 testing guideline in breast cancer was updated in 2018 to address issues on interpretation of uncommon results using dual-probe in situ hybridization according to the 2013 guideline.To assess impact of the 2018 guideline on breast cancer with equivocal HER2 immunohistochemistry results.We retrospectively reviewedA total of 1666The 2018 guideline eliminated

PURPOSE: Axillary treatment strategies for the young woman with early-stage, clinically node-negative breast cancer undergoing upfront surgery found to have 1–3 positive sentinel lymph nodes (SLNs) differ significantly after BCT and mastectomy. Here we compare axillary lymph node dissection (ALND) and regional nodal irradiation (NRI) rates between women electing breast-conservation therapy (BCT) versus mastectomy. METHODS: From 2010–2016, women, age

Purpose Cosmetic outcomes and rate of implant loss are poorly characterized among patients with breast cancer with previous breast augmentation (BA) who undergo breast-conservation therapy (BCT). Here we determine capsular contracture and implant loss frequency after BCT among patients receiving contemporary whole-breast radiation therapy (RT). Methods and Materials Patients with breast cancer with a history of BA presenting to our institution from January 2006 to January 2017 who elected for BCT were included. Seventy-one breast cancers in 70 patients with a history of BA electing for BCT were retrospectively identified. Clinicopathologic, treatment, and outcome variables were examined. Whole-breast RT included conventional and hypofractionated schedules with and without a boost. Rates of implant loss and cosmetic outcomes among patients who did and did not develop a new/worse contracture based on physician assessment were compared. Results In the study, 54.9% of patients received radiation using hypofractionated whole-breast tangents; 81.7% received a boost. In addition, 18 out of 71 cases (25.4%) developed a new/worse contracture after BCT with a mean follow-up of 1.9 years. Furthermore, 9 out of 71 cases (12.7%) were referred to a plastic surgeon for revisional surgery. There were no implant-loss cases. On univariate analysis, implant location, time from implant placement to diagnosis, RT type, RT boost, body mass index, and tumor size were not associated with new/worse contracture. Of 12 patients with existing contracture, only 2 developed worsening contracture. Physician assessment of cosmetic outcome after BCT was noted to be excellent or good for 87.4% of patients. Conclusions BCT for breast cancer patients with prior history of BA has a low risk of implant loss. Hypofractionated RT does not adversely affect implant outcomes. Patients should be counseled regarding risk for capsular contracture, but the majority have good/excellent outcome; BA does not represent a contraindication to BCT.

Background Disparities persist in the receipt of breast reconstruction after mastectomy, and little is known about the nature of communication received by patients and potential variations that may exist. Methods Women with early-stage breast cancer (stages 0 to II) diagnosed between July of 2013 and September of 2014 were identified through the Georgia and Los Angeles Surveillance, Epidemiology, and End Results registries and surveyed to collect additional data on demographics, treatment, and decision-making experiences. Treating general/oncologic surgeons were also surveyed. Primary outcomes measures included self-reported communication-related measures on receipt of information on breast reconstruction and on the receipt of breast reconstruction. Results The authors analyzed 936 women who underwent mastectomy for unilateral breast cancer. Four hundred eighty-four (51.7 percent) underwent mastectomy with reconstruction. Women who were older and for whom English was not their primary spoken language had lower odds of being informed by a doctor about breast reconstruction. Ultimately, women who were older, were Asian, had invasive disease, had bronchitis/emphysema, and had lower income were less likely to undergo breast reconstruction. Breast reconstruction was performed more often in patients undergoing bilateral mastectomies (OR, 3.27; 95 percent CI, 2.26 to 4.75). Women cared for by surgeons with higher volumes of breast cancer patients (≥51 patients per year) were more likely to undergo breast reconstruction (OR, 2.43; 95 percent CI, 1.40 to 4.20). Conclusion To eliminate existing disparities, increased efforts should be made in consultations for surgical management of breast cancer to provide information to all patients regarding the option of breast reconstruction, the possibility of immediate reconstruction, and insurance coverage of all stages of reconstruction.

BACKGROUND: Many factors influence decisions regarding choice of breast-conserving surgery (BCS) versus mastectomy with reconstruction for early invasive breast cancer. The purpose of this study was to compare patient satisfaction following BCS and mastectomy with implant reconstruction (M-iR) utilizing the BREAST-Q patient-reported outcome measure. METHODS: Women with stage I or II breast cancer undergoing BCS or M-iR who completed a BREAST-Q from 2010 to 2016 were identified by retrospective review of a prospective database. Baseline characteristics were compared, and linear mixed models were used to analyze associations with BREAST-Q scores over time. RESULTS: Our study group was composed of 3233 women; 2026 (63%) had BCS, 123 (3.8%) had nipple-sparing mastectomy, and 1084 (34%) had skin-sparing or total mastectomy. Median time from surgery to BREAST-Q was 205 days for BCS and 639 days for M-iR (p

A breast mass is the most common presenting symptom among patients in a breast clinic. The presence of a breast mass can cause a great deal of anxiety in women, as well as their physicians. The differential diagnosis of a palpable breast abnormality is broad, although the majority of breast masses are benign. The responsibility of the physician who is evaluating a breast mass is to exclude the presence of malignancy. Once cancer is ruled out, the physician should then attempt to provide an accurate diagnosis, appropriate treatment, and reassurance to the patient. This chapter discusses the assessment of normal breast physiology, identification of a breast mass, evaluation of the various classifications of breast mass (e.g., dominant mass with clinically benign features and dominant mass with suspicious features), differential diagnosis and management of common benign breast masses (e.g., cysts, fibroadenomas, phyllodes tumors, hamartomas, fat necrosis), and the risk of breast cancer associated with benign breast lesions. The chapter also discusses the diagnosis and management of a breast mass in male patients. Tables outline breast lesions that may present as a palpable abnormality, factors used for the assessment of breast cancer risk, physical characteristics of benign and malignant breast masses, the accuracy of fine-needle aspiration, and benign breast lesions by category. Figures illustrate diagnostic procedures, the anatomy of the human breast, visual inspection of the breasts, physical examination of the breasts, breast palpation technique, the evaluation and management of a new breast mass, and the identification of cysts. This review contains 10 figures, 14 tables, and 64 references. Keywords: breast mass, lobuloalveolar development, subareolar nodularity, parenchyma (glandular elements), stromal tissue, ovarian graafian follicles

The National Comprehensive Cancer Network (NCCN) endorses sentinel lymph node biopsy (SLNB) in patients with clinically positive axillary nodes who downstage after neoadjuvant chemotherapy (NAC). In this study, we compared the accuracy of post-NAC MRI to clinical exam alone in predicting pathologic status of sentinel lymph nodes in cN1 patients. We identified patients with T0-3, N1 breast cancer who underwent NAC and subsequent SLNB from March 2014 to July 2017. Patients were grouped based on whether a post-NAC MRI was done. MRI accuracy in predicting SLN status was assessed versus clinical exam alone. A total of 450 patients met initial study criteria; 269 were analyzed after excluding patients without biopsy-confirmed nodal disease, palpable disease after NAC, and failed SLN mapping. Median age was 49 years. Post-NAC MRI was done in 68% (182/269). Patients undergoing lumpectomy vs mastectomy more frequently received a post-NAC MRI (88 vs 54%, p

Background: Obese women who carry a mutation in the DNA repair enzymes BRCA1 and/or BRCA2 are at a greater risk of developing breast cancer compared with lean BRCA1/2 mutation carriers. Causative factors that drive the increased penetrance of breast cancer in obese women are poorly characterized. Previously, we showed that BMI was positively correlated with DNA damage in breast epithelium of BRCA mutation carriers. We hypothesized that obesity-associated dysfunctional adipose tissue may cause DNA damage in neighboring breast epithelial cells. If true, this would provide evidence for the initial insults associated with increased risk of tumor formation in obese women. Methods: To test the effect of locally secreted factors on DNA damage induction, conditioned media was collected over 24 hours from primary breast adipose explants obtained from lean and obese women. Conditioned media was used to treat normal breast epithelial cells (MCF10A) harboring a heterozygous BRCA1 mutation or wildtype for BRCA. Immunofluorescence (IF) staining of the DNA damage marker ƴH2AX was carried out after treatment. Cell line findings were validated in primary breast epithelial organoids isolated by collagenase digestion of breast tissue obtained from the clinic. Additionally, RNA-seq was conducted on primary breast epithelial organoids isolated from lean and obese women to identify potential drivers of gene expression differences associated with obesity and DNA damage. Results: Conditioned media from obese breast adipose tissue stimulated DNA damage in BRCA mutant breast epithelial cells while lean conditioned media did not have this effect. Similar findings were made in primary breast epithelial organoids, suggesting a role for locally secreted factors in mediating DNA damage. Ingenuity Pathway Analysis of RNA-seq data from lean and obese primary breast organoids identified several upstream regulators of gene expression differences, including signaling by estradiol and pro-inflammatory cytokines, both of which are elevated in obese breast tissue and are known inducers of DNA damage. Conclusions: These data show for the first time that local factors produced by obese breast adipose tissue induce breast epithelial cell DNA damage. Our results suggest that therapies targeting weight or dysfunctional breast adipose tissue may reduce the increased DNA damage observed in obese BRCA mutation carriers and thereby decrease tumor formation in this high-risk population of women.

The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated that axillary lymph node dissection (ALND) may be omitted for women with two or fewer positive sentinel nodes (SLNs) undergoing breast-conservation therapy (BCT). Lobular histology comprises a minority of patients, and applicability to these discohesive cancers has been questioned. From August 2010 to March 2017, patients undergoing BCT for cT1-2N0 cancer with positive SLNs were prospectively managed with ALND for three or more positive SLNs or gross extracapsular extension (ECE). In this study, clinicopathologic characteristics and nodal burden were compared between pure/mixed invasive lobular cancer (ILC) and invasive ductal cancer (IDC) patients. Among 813 consecutive patients, 104 (12.8%) had ILC and 709 (87.2%) had IDC. ILC was more often multifocal and low grade, and less frequently had lymphovascular invasion (all p

The understanding of margins has changed with awareness that factors in addition to tumor burden such as tumor biology and the effectiveness of systemic therapy impact local control in invasive cancer. This chapter reviews pathologic techniques of margin assessment and what is known about the relationship between margin width and local control for invasive carcinoma and intraductal carcinoma.

10517 Background: Breast and ovarian cancer patients increasingly undergo germline genetic testing. While studies suggest a greater chemotherapy benefit for carriers of BRCA1/2 pathogenic variants, little is known about whether pathogenic variants in other genes are associated with cancer mortality. Methods: Georgia and California Surveillance, Epidemiology and End Results (SEER) registry records of women diagnosed with breast cancer or ovarian cancer from 2013-2017 were linked to results of clinical germline genetic testing from four participating laboratories. Patients were included if they linked to a genetic result, had stages I-III breast cancer or I-IV epithelial ovarian cancer and received chemotherapy. Multivariable Cox proportional hazard models were used to examine the association of genetic results, demographic and clinical factors with cancer-specific mortality. Results: 21,348 breast and 4,320 ovarian cancer patients were analyzed with median follow-up of 41 months. Pathogenic variants were present in 12% of patients with estrogen and progesterone receptor-positive, HER2-negative breast cancer, 9% with HER2-positive breast cancer, 17% with triple-negative breast cancer and 18% with ovarian cancer. Pathogenic variants were most common in BRCA1/2, CHEK2, PALB2, ATM and BRIP1. Among triple-negative breast cancer patients, mortality was lower with pathogenic variants in BRCA1 (hazard ratio (HR) 0.27, 95% confidence interval (CI) 0.17-0.45) and genes other than BRCA1/2 (HR 0.33, CI 0.13-0.81) versus no pathogenic variant. Genetic results were not associated with mortality in other breast cancer subtypes. Among ovarian cancer patients, mortality was lower with pathogenic variants in BRCA2 (HR 0.36, CI 0.26-0.49) and in genes other than BRCA1/2 (HR 0.48, CI 0.33-0.70). Conclusions: Among breast and ovarian cancer patients treated with chemotherapy, those with germline pathogenic variants in several cancer-associated genes had equivalent or lower short-term mortality than those testing negative. These results may guide patient counseling and clinical trial design.

Background: Obesity is a risk factor for breast cancer development in women who carry a mutation in the DNA repair enzymes BRCA1 or BRCA2. Previously, we found that obesity was positively associated with DNA damage in breast epithelium from BRCA mutation carriers. Furthermore, factors secreted by obese breast adipose tissue stimulated DNA damage in BRCA mutant breast epithelial cells, suggesting a cross-talk between breast epithelial cells and the adipose tissue that surrounds them. We hypothesized that leptin, a hormone secreted in abundance by obese adipose tissue, may be a driver of DNA damage and/or decrease capacity for DNA repair in breast epithelial cells. If true, this would provide a molecular target for intervention to reduce the risk of tumor formation in this high-risk population of women. Methods: RNA-seq followed by Ingenuity Pathway Analysis (IPA) was conducted on primary breast epithelial organoids isolated from lean and obese BRCA mutation carriers. Breast adipose tissue obtained from lean and obese women were cultured as explants for 24 hours to produce lean and obese conditioned media (CM). The effect of leptin on DNA damage was assessed in a non-cancerous breast epithelial cell line (MCF10A) carrying a heterozygous BRCA1 mutation. Immunofluorescence staining of the DNA damage marker ƴH2AX was carried out after treatment with leptin (100ng-800ng), CM, or CM+leptin antibody, used to neutralize leptin. To test whether leptin affects DNA repair capacity, BRCA1+/- MCF10A cells were treated with leptin or vehicle and then irradiated (1Gy) to induce DNA damage. Resolution of damage was quantified at 0, 0.5, 4, 12, and 24 hrs post-irradiation. Results: IPA analysis identified leptin signaling as significantly upregulated in breast epithelial organoids from obese women compared with lean women. Both obese CM and leptin treatment induced DNA damage in BRCA1+/- MCF10A cells while lean CM did not have this effect. Neutralizing leptin in obese CM was sufficient to inhibit obese CM-mediated induction of DNA damage. No significant difference was observed between leptin or vehicle treatments on DNA repair capacity after irradiation of BRCA+/- MCF10A cells. Conclusions: These data identify leptin, an adipose-derived hormone, as a novel driver of DNA damage in breast epithelial cells. To date, no studies have elucidated the molecular mechanisms that explain the increased penetrance of breast cancer in obese BRCA mutation carriers compared to lean BRCA mutation carriers. This work suggests that leptin may be a mediator of the link between obesity and breast cancer development in this population. Further studies are warranted to determine if targeting the leptin signaling axis will be an effective risk reduction strategy in BRCA mutation carriers who have excess adiposity.

Importance There is currently no guidance on how to approach surveillance mammography for older breast cancer survivors, particularly when life expectancy is limited. Objective To develop expert consensus guidelines that facilitate tailored decision-making for routine surveillance mammography for breast cancer survivors 75 years or older. Evidence After a literature review of the risk of ipsilateral and contralateral breast cancer events among breast cancer survivors and the harms and benefits associated with mammography, a multidisciplinary expert panel was convened to develop consensus guidelines on surveillance mammography for breast cancer survivors 75 years or older. Using an iterative consensus-based approach, input from clinician focus groups, and critical review by the International Society for Geriatric Oncology, the guidelines were refined and finalized. Findings The literature review established a low risk for ipsilateral and contralateral breast cancer events in most older breast cancer survivors and summarized the benefits and harms associated with mammography. Draft mammography guidelines were iteratively evaluated by the expert panel and clinician focus groups, emphasizing a patient’s risk for in-breast cancer events, age, life expectancy, and personal preferences. The final consensus guidelines recommend discontinuation of routine mammography for all breast cancer survivors when life expectancy is less than 5 years, including those with a history of high-risk cancers; consideration to discontinue mammography when life expectancy is 5 to 10 years; and continuation of mammography when life expectancy is more than 10 years. Individualized, shared decision-making is encouraged to optimally tailor recommendations after weighing the benefits and harms associated with surveillance mammography and patient preferences. The panel also recommends ongoing clinical breast examinations and diagnostic mammography to evaluate clinical findings and symptoms, with reassurance for patients that these practices will continue. Conclusions and Relevance It is anticipated that these expert guidelines will enhance clinical practice by providing a framework for individualized discussions, facilitating shared decision-making regarding surveillance mammography for breast cancer survivors 75 years or older.

Ductal carcinoma in situ (DCIS) is a heterogenous disease. The mainstay of its management is surgery, and lumpectomy with or without radiation therapy (RT) or mastectomy are standard options. Endocrine therapy may be given to maximize risk reduction. With standard treatment, the longterm breast cancer-specific survival is excellent and exceeds 95%. Currently, management strategies are based on standard clinicopathological features. Genomic tools to predict local recurrence have been developed, and prospective studies to evaluate their impact on RT recommendations and outcomes are ongoing. Because of concerns regarding overtreatment of DCIS, there has been much enthusiasm for de-escalating locoregional therapy. RT halves the risk of local recurrence but does not affect survival, and its omission can be considered in low-risk groups. Active surveillance for lowrisk DCIS is being evaluated in 4 prospective trials. The concern regarding these trials is whether the selected "low-risk" cases are truly at low risk, and what threshold of recurrence is considered acceptable. Additionally, it is unclear whether patients will be willing to trade short outpatient procedures for more biopsies, more imaging, and possibly increased concern about recurrence. The clinical relevance and the safety of this approach are yet to be determined.

Purpose: To assess the safety and tolerability of preoperative cryoablation-mediated tumor antigen presentation and/or ipilimumab-mediated immune modulation in women with operable breast cancer. Experimental Design: In this pilot study, 19 women with breast cancer for whom mastectomy was planned were treated with preoperative tumor cryoablation (n = 7), single-dose ipilimumab at 10 mg/kg (n = 6), or both (n = 6). The primary outcome for this pilot study was safety/tolerability as defined as freedom from delays in pre-planned, curative-intent mastectomy. Exploratory studies of immune activation were performed on peripheral blood and tumor. Results: Preoperative cryoablation and/or ipilimumab were safe and tolerable, with no delays in pre-planned surgery. Grade III toxicity was seen in 1 of 19 (unrelated rash after ipilimumab). Combination therapy was associated with sustained peripheral elevations in: Th1-type cytokines, activated (ICOS+) and proliferating (Ki67+) CD4+ and CD8+ T cells, and posttreatment proliferative T-effector cells relative to T-regulatory cells within tumor. Conclusions: Preoperative cryoablation and single-dose ipilimumab are safe alone or in combination with no surgical delays incurred. Potentially favorable intratumoral and systemic immunologic effects were observed with the combination, suggesting the possibility for induced and synergistic antitumor immunity with this strategy. Clin Cancer Res; 22(23); 5729–37. ©2016 AACR.

* This author contributed to the development and review of this manuscript but is unable to endorse the request for NIH funding . It is a tremendously exciting time for the cancer community. Thanks to research, we are making significant progress against the many diseases we

There is no consensus on adequate negative margins in breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS). We systematically reviewed the evidence on margins in BCS for DCIS.A study-level meta-analysis of local recurrence (LR), microscopic margin status and threshold distance for negative margins. LR proportion was modeled using random-effects logistic meta-regression (frequentist) and network meta-analysis (Bayesian) that allows for multiple margin distances per study, adjusting for follow-up time.Based on 20 studies (LR: 865 of 7883), odds of LR were associated with margin status [logistic: odds ratio (OR) 0.53 for negative vs. positive/close (p 0.001); network: OR 0.45 for negative vs. positive]. In logistic meta-regression, relative to0 or 1 mm, ORs for 2 mm (0.51), 3 or 5 mm (0.42) and 10 mm (0.60) showed comparable significant reductions in the odds of LR. In the network analysis, ORs relative to positive margins for 2 (0.32), 3 (0.30) and 10 mm (0.32) showed similar reductions in the odds of LR that were greater than for0 or 1 mm (0.45). There was weak evidence of lower odds at 2 mm compared with0 or 1 mm [relative OR (ROR) 0.72, 95 % credible interval (CrI) 0.47-1.08], and no evidence of a difference between 2 and 10 mm (ROR 0.99, 95 % CrI 0.61-1.64). Adjustment for covariates, and analyses based only on studies using whole-breast radiotherapy, did not change the findings.Negative margins in BCS for DCIS reduce the odds of LR; however, minimum margin distances above 2 mm are not significantly associated with further reduced odds of LR in women receiving radiation.

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

Performing a sentinel lymph node biopsy (SLNB) is the standard of care for axillary nodal staging in patients with invasive breast cancer and clinically negative nodes. The procedure provides valuable staging information with few complications when performed by experienced surgeons. However, variation in proficiency exists for this procedure, and a great amount of experience is required to master the technique, especially when faced with challenging cases. The purpose of this paper was to provide a troubleshooting guide for commonly encountered technical difficulties in SLNB, and offer potential solutions so that surgeons can improve their own technical performance from the collective knowledge of experienced specialists in the field. Information was obtained from a convenience sample of six experienced breast cancer specialists, each actively involved in training surgeons and residents/fellows in SLNB. Each surgeon responded to a structured interview in order to provide salient points of the SLNB procedure. Four of the key opinion surgical specialists provided their perspective using technetium-99 m sulfur colloid, and two shared their experience using blue dye only. Distinct categories of commonly encountered problem scenarios were presented and agreed upon by the panel of surgeons. The responses to each of these scenarios were collected and organized into a troubleshooting guide. We present a compilation of ‘tips’ organized as a troubleshooting guide to be used to guide surgeons of varying levels of experience when encountering technical difficulties with SLNB.

Purpose The objective of this study was to determine whether the 21-gene Recurrence Score (RS) provides clinically meaningful information in patients with de novo stage IV breast cancer enrolled in the Translational Breast Cancer Research Consortium (TBCRC) 013. Patients and Methods TBCRC 013 was a multicenter prospective registry that evaluated the role of surgery of the primary tumor in patients with de novo stage IV breast cancer. From July 2009 to April 2012, 127 patients from 14 sites were enrolled; 109 (86%) patients had pretreatment primary tumor samples suitable for 21-gene RS analysis. Clinical variables, time to first progression (TTP), and 2-year overall survival (OS) were correlated with the 21-gene RS by using log-rank, Kaplan-Meier, and Cox regression. Results Median patient age was 52 years (21 to 79 years); the majority had hormone receptor–positive/human epidermal growth factor receptor 2 (HER2)–negative (72 [66%]) or hormone receptor–positive/HER2-positive (20 [18%]) breast cancer. At a median follow-up of 29 months, median TTP was 20 months (95% CI, 16 to 26 months), and median survival was 49 months (95% CI, 40 months to not reached). An RS was generated for 101 (93%) primary tumor samples: 22 (23%) low risk (< 18), 29 (28%) intermediate risk (18 to 30); and 50 (49%) high risk (≥ 31). For all patients, RS was associated with TTP (P = .01) and 2-year OS (P = .04). In multivariable Cox regression models among 69 patients with estrogen receptor (ER)–positive/HER2-negative cancer, RS was independently prognostic for TTP (hazard ratio, 1.40; 95% CI, 1.05 to 1.86; P = .02) and 2-year OS (hazard ratio, 1.83; 95% CI, 1.14 to 2.95; P = .013). Conclusion The 21-gene RS is independently prognostic for both TTP and 2-year OS in ER–positive/HER2-negative de novo stage IV breast cancer. Prospective validation is needed to determine the potential role for this assay in the clinical management of this patient subset.

More than one-third of American adults are obese, and an elevated body mass index (BMI) is postulated to reduce the sensitivity of the clinical evaluation of the axilla. Clinical nodal examination is important in allocating breast cancer patients to appropriate axillary management. This study sought to determine whether BMI influences the rate of nodal positivity in women designated clinically as node-negative (cN0) by physical examination. Breast cancer patients deemed cN0 who underwent sentinel lymph node biopsy (SLNB) from February 2006 to December 2011 were identified from a prospectively maintained database. Clinicopathologic features including BMI and axillary surgery results were recorded and compared among pathologically node-negative and node-positive patients. Overall, 5142 cN0 patients underwent 5262 SLNB procedures during the study period. Nearly one-third of the patients (28 %) were obese (BMI, >30 kg/m2). A positive SLN was identified in 25 % of the patients, and 84 % proceeded to axillary lymph node dissection. Predictors of SLN positivity included younger age, larger tumor size, high nuclear grade, multifocality, and lymphovascular invasion. An increased BMI did not correlate with a higher likelihood of SLN positivity (p = 0.6). The likelihood of cN0 patients having a high burden of axillary metastases (>3 positive nodes) was 4 % overall and, similarly, did not differ according to BMI (p = 0.4). Elevated BMI was not associated with a higher likelihood of SLN positivity or heavy nodal disease burden among women staged as cN0 by physical exam. These findings indicate that physical examination is appropriate and sufficient for preoperative axillary evaluation of women undergoing initial surgery regardless of patient BMI.

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

The Surgery Versus Active Monitoring for Low-Risk DCIS (LORIS) trial is studying the safety of monitoring core-biopsy diagnosed low-risk ductal carcinoma in situ (DCIS) without excision. We sought to determine the incidence and characteristics of synchronous invasive carcinoma found in LORIS-eligible women who underwent excision, as this knowledge is essential in assessing the safety of observation alone. Women meeting LORIS eligibility criteria (age ≥46 years, screen-detected calcifications, non-high-grade DCIS diagnosed by core biopsy, absence of nipple discharge, or strong family history of breast cancer) who underwent surgical excision from 2009 to 2012 were identified. Histologic findings of excision specimens were reviewed. Overall, 296 LORIS-eligible cases were identified; 58 (20 %) had invasive carcinoma on final pathology (90 % invasive ductal, 78 % >1 mm in size, 21 % high grade, 3 % triple negative, 9 % HER2 amplified). Of these, 18 (31 %) were pT1b or larger and 3 (5 %) were pN1. Among eligible upgraded cases, 90 % received radiation, 89 % received endocrine therapy, and 18 % were recommended chemotherapy. Women upgraded to invasive carcinoma were more likely to have intermediate-grade DCIS on core biopsy and to have undergone mastectomy. Among LORIS-eligible women, 20 % had invasive carcinoma at surgical excision that was heterogeneous in grade, size, and receptor status. Information gained from surgical excision influenced receipt of adjuvant radiation and endocrine therapy in most patients, and indicated benefit from chemotherapy in 18 % of patients. Surgical excision is warranted until additional risk stratification is available to identify a cohort of DCIS patients at lower risk for clinically significant synchronous invasive carcinoma.

The American College of Surgeons Oncology Group Z0011 trial demonstrated the safety of omitting axillary lymph node dissection (ALND) for women with fewer than three positive sentinel lymph nodes (SLNs) who are undergoing breast-conservation therapy (BCT). Because most of the women were postmenopausal with estrogen receptor (ER) positive cancers, applicability of ALND for younger patients and those with triple-negative (TN) or human epidermal growth factor receptor 2 (HER2) overexpressing (HER2+) tumors remains controversial.From August 2010 to December 2015, patients undergoing BCT for cT1-2N0 disease and found to have positive SLNs were prospectively followed. Axillary lymph node dissection was indicated for more than two positive SLNs or gross extracapsular extension. Clinicopathologic characteristics, axillary surgery, nodal burden, and outcomes were compared between the high-risk patients (TN, HER2+, or age 50 years) and the remaining patients, termed average risk patients.Among 701 consecutive patients, 242 (35 %) were high risk: 31 (13 %) with TN, 48 (20 %) with HER2+, 130 (54 %) with age less than 50 years, and 33 (14 %) with more than one high-risk feature. The remaining 459 patients (65 %) were average risk. The high-risk patients were younger, had higher-grade tumors (p 0.0001), and more often had abnormal nodes imaged (p = 0.02). In this study, SLNB alone was performed for 85 % high-risk versus 82 % average-risk cases (p = 0.39). A median of four versus three SLNs were excised (p = 0.04), and both groups had a median of one positive SLN. Additional positive nodes at ALND were found in 62 % high-risk patients versus 65 % average-risk patients (p = 0.8), with a median of three positive nodes in both groups. During a median follow-up period of 31 months, no patients experienced isolated axillary recurrences.Axillary lymph node dissection was no more likely to be indicated for high-risk patients. For patients undergoing ALND, the nodal burden was similar. For patients otherwise meeting the American College of Surgeons Oncology Group (ACOSOG) Z0011 clinical eligibility criteria, ALND is not indicated on the basis of age or subtype.

Background To use clinical and MRI radiomic features coupled with machine learning to assess HER2 expression level and predict pathologic response (pCR) in HER2 overexpressing breast cancer patients receiving neoadjuvant chemotherapy (NAC). Methods This retrospective study included 311 patients. pCR was defined as no residual invasive carcinoma in the breast or axillary lymph nodes (ypT0/isN0). Radiomics/statistical analysis was performed using MATLAB and CERR software. After ROC and correlation analysis, selected radiomics parameters were advanced to machine learning modelling alongside clinical MRI-based parameters (lesion type, multifocality, size, nodal status). For predicting pCR, the data was split into a training and test set (80:20). Findings The overall pCR rate was 60.5% (188/311). The final model to predict HER2 heterogeneity utilised three MRI parameters (two clinical, one radiomic) for a sensitivity of 99.3% (277/279), specificity of 81.3% (26/32), and diagnostic accuracy of 97.4% (303/311). The final model to predict pCR included six MRI parameters (two clinical, four radiomic) for a sensitivity of 86.5% (32/37), specificity of 80.0% (20/25), and diagnostic accuracy of 83.9% (52/62) (test set); these results were independent of age and ER status, and outperformed the best model developed using clinical parameters only (p=0.029, comparison of proportion Chi-squared test). Interpretation The machine learning models, including both clinical and radiomics MRI features, can be used to assess HER2 expression level and can predict pCR after NAC in HER2 overexpressing breast cancer patients. Funding NIH/NCI (P30CA008748), Susan G. Komen Foundation, Breast Cancer Research Foundation, Spanish Foundation Alfonso Martin Escudero, European School of Radiology.

The 2014 publication of the Society of Surgical Oncology-American Society for Radiation Oncology (SSO-ASTRO) Consensus Guideline on Margins for Breast-Conserving Surgery recommended a negative margin definition of no ink on tumor. Adoption of this guideline would represent a major change in surgical practice that could lower the rates of reoperation.To assess changes in reoperation rates after publication of the SSO-ASTRO guideline.A systematic search of Embase, PREMEDLINE, Evidence-Based Medicine Reviews, Scopus, and Web of Science for biomedical literature published from January 2014 to July 2019 was performed. This search was supplemented by web searches and manual searching of conference abstracts.Included studies compared the reoperation rates in preguideline vs postguideline cohorts (actual change), retrospectively applied the SSO-ASTRO guideline to a preguideline cohort (projected change), or described the economic outcomes of the guideline.Study characteristics and reoperation rates were extracted independently by 2 reviewers. Odds ratios (ORs) were pooled by random effects meta-analysis. Analyses were stratified by study setting (institutional or population) and preguideline accepted margins. The economic outcomes of the guideline were summarized narratively. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed.Odds ratios for postguideline vs preguideline reoperation rates.From 1114 citations, 30 studies (with 599 016 participants) reported changes in reoperation rates. Studies included a median (range) of 487 (100-521 578) participants, and 20 studies were undertaken in the US, 6 in the UK, 3 in Canada, and 1 in Australia. Among 21 studies of actual changes, pooled ORs showed a statistically significant reduction in reoperation, with an OR lower in institution-based studies than in population-based studies (OR, 0.62 [95% CI, 0.52-0.74] vs 0.76 [95% CI, 0.72-0.80]; P = .04 for subgroup differences). Among 9 studies of projected changes, the pooled OR was lower for preguideline margin thresholds of 2 mm or more compared with 1 mm (OR, 0.47 [95% CI, 0.40-0.56] vs 0.85 [95% CI, 0.79-0.91; P .001 for subgroup differences). Projected changes were likely to overestimate actual changes. Six studies that estimated the postguideline economic outcome found the guideline to be potentially cost saving, with a median (range) saving of US $3540 ($1800-$25 650) per woman avoiding reoperation.This study found a decrease in reoperation rates after the publication of the SSO-ASTRO guideline; this reduction was greater at an institutional level than a population level, the latter reflecting the differences in guideline adoption between centers. These early outcomes may be conservative estimates of longer-term implications.

273 Background: Genetic testing is increasingly central to breast and ovarian cancer prevention and treatment. Yet, little is known about trends and disparities in receipt of testing and test results after diagnosis. Methods: We linked all female patients with breast or ovarian cancer diagnosed from 2013-2017 in Georgia and California and reported to SEER registries to genetic testing results from four laboratories (Ambry Genetics, GeneDx, Invitae, Myriad Genetics). We combined test results from all labs with SEER data. We classified a test as a multigene panel (MGP) if it included other genes in addition to BRCA1/2. We grouped pathogenic variants (PVs) by level of evidence that supported clinical testing: BRCA1/2; other genes associated with well-established syndromes (syndromic genes); genes whose cancer association is less certain (emerging genes); and any other tested genes (other genes). We categorized patients with a variant of unknown significance (VUS) in any gene but no PVs as VUS-only. We examined trends in receipt of testing and test results overall and by race/ethnic groups. Results: One quarter (25.5%) of 198,001 breast cancer patients, and 34.5% of 15,461 ovarian cancer patients had genetic tests. Test rates increased by only 2% annually; while the number of genes tested per patient increased by 28%. The mean number of genes tested rose from 10 to 35 during the study period. In early 2013, 18.3% of testers had a PV or VUS result, which increased to 37.2% in late 2017. The upward trend was largely due to increase in VUS-only findings. The proportion of tested breast cancer patients with any PV increased from 9.1% to 9.9%: PVs in BRCA1/2 decreased from 7.5% to 5.0% (p

e12525 Background: Optimal approach to early-stage breast cancer (BC) management in women ≥70y is unclear. Studies have demonstrated improved local control but no survival advantage with use of radiation therapy (RT) after breast-conservation therapy (BCT). The impact on survival of other management decisions, including breast procedure, axillary staging (AS), systemic treatment, and patient comorbidities is unknown. We evaluate the effect of each treatment decision on overall survival (OS), disease-free survival (DFS), and breast-cancer specific survival (BCSS). Methods: Patients age ≥70y with cT1N0/ER+/HER2- tumors undergoing surgery from 2011-2013 were identified from a prospectively maintained, single-institution database. Clinicopathologic features were evaluated. 10-year estimated mortality from comorbidity was calculated using a Suemoto index (SI). Univariate and multivariable associations were assessed using Cox modeling. Kaplan-Meier method was used to estimate OS and DFS. Results: 338 patients were identified: 312 (92%) underwent BCT; 26 (8%) had mastectomy. Median age was 75.5y (70-101); median tumor size was 1.0cm (0.1-1.9); median SI was 42.5(22-99). With a median follow-up of 60 mos, 25 patients died—1 from BC, for an OS rate of 92.8% and BCSS of 99.7%. 9 patients developed a locoregional recurrence and 1 developed distant recurrence, representing a 5-year DFS rate of 97.8%. There were no differences in DFS by age groups (≤75, 76-80, > 80; p = 0.1). On univariate analysis, DFS did not vary by age, breast procedure, or receipt of chemotherapy. It was improved in those who had AS and a lower SI (p < 0.01). OS was better in those patients who had AS, had recurrence score performed and had radiation therapy, reflecting lower SI. On multivariable analysis, lack of AS (HR 10.5, p < 0.01) and higher SI (HR 1.03, p < 0.01) were the only variables associated with worse OS. Lack of AS became non-significant in those > 80y. No treatment decision led to improved BCSS. When comparing patients with local or systemic recurrence vs those without recurrence, there was no difference in OS (p = 0.4) or BCSS (p = NS). Conclusions: Decisions in early-stage BC in the elderly are complex due to competing morbidities. While DFS and OS may vary based on treatment variables, no specific care component affected BCSS. Treatment discussions in elderly BC patients should emphasize the risks/benefits of each care component, taking into consideration the patient’s comorbidities and allowing for the patient’s understanding of outcomes and quality of life.

524 Background: The 21-gene Oncotype DX Breast Recurrence Score multigene assay (RS) identifies women with ER positive, HER negative, axillary node-negative breast cancer (BC) for whom chemotherapy provides no invasive disease-free survival benefit compared to endocrine therapy alone. International adoption of RS testing is limited by cost and resource availability. We created a supervised statistical machine learning model using standard clinicopathologic data to predict RS risk category in women > 50 years old. Methods: From 2012 to 2018, women with ER positive, HER2 negative, pathologically node-negative BC of all ages were retrospectively identified from a prospective institutional database. Standard clinicopathologic data and RS were collected. Per institutional protocol, RS are ordered for all early-stage, ER positive tumors > 5 mm. Data were randomly split into training (n=3755) and validation sets (n=1609). A random forest model with 500 trees was developed on the training set, then evaluated on the validation set. Model predictors included age, tumor size, histologic subtype, hormone receptor status, lymphovascular invasion, and overall grade. The model was used to predict RS category (low risk: RS ≤ 25, high risk: RS > 25) in women > 50 years old. Results: 5364 unique tumors in 5189 women were identified. 3731 (70%) of tumors were identified in women > 50 years; median age was 63 years (IQR 57-69). In women > 50, median tumor size was 12 mm (IQR 9-17). Most tumors were invasive ductal (79%), low or intermediate grade (79%), and LVI was absent in 82% of tumors. Median ER staining by IHC was 95%; 28% of tumors had negative or weakly positive PR staining (1-20%). The model correctly classified 96.8% of patients as low risk (95% CI: 95.7-97.7). Negative predictive value for identifying low risk category was also high (92.3%, 90.7-93.6). Sensitivity for identifying high-risk women was 44.7% (37.4-52.1) and positive predictive value was 67.2% (58.2-75.3). A classification table on the validation set includes tumors with complete data available, including predictors and RS. Conclusions: Our model was highly specific (96.8%) for identifying women > 50 with RS ≤ 25 who do not benefit from adjuvant chemotherapy. This model may be utilized in lieu of RS testing if cost and availability are prohibitive. True RS > 25 was not as well predicted. The model will be refined following pathologic review of discordant cases to reduce false negatives. [Table: see text]

542 Background: Opioid-induced immunomodulation may be of particular importance in triple negative breast cancer (TNBC) where an immune response is associated with improved outcome and response to immunotherapy. We evaluated the association between intraoperative opioids and outcomes in a large TNBC cohort. Methods: Consecutive patients with stage I-III primary TNBC treated between 03/2010 and 12/2016 were identified from our prospectively maintained database. Total intraoperative opioid dose was extracted from anesthetic records and converted to oral morphine milligram equivalents (MME) (10 MME = 50 mcg fentanyl IV). Univariable and multivariable (MVA) Cox proportional hazards analysis (adjusting for relevant clinicopathological features, (neo)adjuvant therapy, anesthesia technique and morbidity score), were performed to quantify the association between opioid exposure and recurrence-free survival (RFS) and overall survival (OS). Results: 1143 patients were included. Median age was 54 years (IQR 45, 64). 911 (80%) had ductal histology, 359 (31%) had nodal metastases, and 1070 (94%) were poorly differentiated. 781 (68%) received adjuvant chemotherapy and 313 (27%) received neoadjuvant chemotherapy. 525 (46%) received total intravenous anesthesia and 618 (54%) had general anesthesia. Median intraoperative opioid dose was 30 MME (IQR 20, 60). 5-year RFS was 81% (95% CI 79%-84%), 5-year OS was 86% (95% CI 84%-88%). In MVA, higher opioid administration was associated with favorable RFS but did not significantly affect OS (Table). Conclusions: Our study is the first to directly evaluate intraoperative opioid administration in TNBC and suggests a protective effect on RFS. Future work will focus on elucidating the underlying mechanism for this effect, including possible modulation of endogenous opioid signaling pathways and immunologic correlates. [Table: see text]

One in five patients undergoing initial lumpectomy for invasive breast cancer subsequently undergoes re-excision or mastectomy. A lack of clarity of when to re-excise based on lumpectomy margin width contributes to this high rate of reoperation. We sought to determine the impact of the Society of Surgical Oncology (SSO) and American Society of Radiation Oncologist (ASTRO) margin guideline on reoperation rates after lumpectomy. The guideline recommended omission of routine re-excision in specimens with “no ink on tumor”. A systematic literature review was performed. For eligible studies, a random-effects model was used for a meta-analysis of lumpectomy re-excision prevalence before and after publication of the SSO-ASTRO margin guideline. Study heterogeneity was measured by the Cochran’s Q test. Five institutional, one population-based, and one national registry study met inclusion requirements. Sample size per study ranged from 237 to 26,102. There was significant interstudy heterogeneity (Q = 19.779; p = 0.003). Pooled re-excision prevalence was 22% (confidence interval [CI] 20–23) before and 14% (CI 12–15) after guideline publication. With the pre-guideline re-excision prevalence used as the reference value, the associated odds ratio for re-excision after the guideline was 0.65 (CI 0.54–0.78; p

BACKGROUND Black women with breast cancer have lower survival rates and higher recurrence rates in comparison with white women. This study compared treatment and survival outcomes for black and white women at a highly specialized tertiary care cancer center. METHODS An institutional review board-approved, retrospective institutional database review was performed to identify all black women treated for invasive breast cancer between 2005 and 2010. Women with a prior history of breast cancer, stage IV cancer, or bilateral breast cancer were excluded. White women had similar exclusion criteria applied and were then matched to black women 1:1 by age and diagnosis year. Clinicopathologic and treatment variables were compared by race. Kaplan-Meier methodology was used to estimate overall survival (OS) and disease-free survival (DFS); a multivariable analysis was conducted with Cox regression models. RESULTS The study group consisted of 1332 women (666 black). The median tumor size was larger in black women (1.6 vs 1.3 cm; P

Obesity increases the risk of hormone receptor–positive breast cancer in postmenopausal women. Levels of aromatase, the rate-limiting enzyme in estrogen biosynthesis, are increased in the breast tissue of obese women. Both prostaglandin E(2) (PGE(2)) and hypoxia-inducible factor 1α (HIF-1α) contribute to the induction of aromatase in adipose stromal cells (ASCs). Sirtuin 1 (SIRT1) binds, deacetylates, and thereby inactivates HIF-1α. Here, we sought to determine whether SIRT1 also plays a role in regulating aromatase expression. We demonstrate that reduced SIRT1 levels are associated with elevated levels of acetyl–HIF-1α, HIF-1α, and aromatase in breast tissue of obese compared with lean women. To determine whether these changes were functionally linked, ASCs were utilized. In ASCs, treatment with PGE(2), which is increased in obese individuals, down-regulated SIRT1 levels, leading to elevated acetyl–HIF-1α and HIF-1α levels and enhanced aromatase gene transcription. Chemical SIRT1 activators (SIRT1720 and resveratrol) suppressed the PGE(2)-mediated induction of acetyl–HIF-1α, HIF-1α, and aromatase. Silencing of p300/CBP-associated factor (PCAF), which acetylates HIF-1α, blocked PGE(2)-mediated increases in acetyl–HIF-1α, HIF-1α, and aromatase. SIRT1 overexpression or PCAF silencing inhibited the interaction between HIF-1α and p300, a coactivator of aromatase expression, and suppressed p300 binding to the aromatase promoter. PGE(2) acted via prostaglandin E2 receptor 2 (EP(2)) and EP(4) to induce activating transcription factor 3 (ATF3), a repressive transcription factor, which bound to a CREB site within the SIRT1 promoter and reduced SIRT1 levels. These findings suggest that reduced SIRT1-mediated deacetylation of HIF-1α contributes to the elevated levels of aromatase in breast tissues of obese women.

Cancers classified as "special histologic subtypes" are felt to have a good prognosis. We used the 21-gene Oncotype DX Breast Recurrence Score610,350 tumor specimens examined in the Genomic Health clinical laboratory from 2/2004 to 8/2017 were included. Specimen histology was classified centrally using a single HE slide and World Health Organization criteria. RS distribution (low 18, intermediate 18-30, and high ≥ 31) was compared among histologic subtypes.Median patient age was 60 years (IQR 51-67); 80% were node negative. Most patients had low RS results (59.2%); only 9.5% had high results. The lowest mean RS was seen in the papillary subtype (11); the highest in the IDC group (18.4). Mean RS for all special subtypes was lower than that of IDC patients. When the high RS threshold was decreased from 31 to 25, as used in the TAILORx and RxPONDER trials, the number of high RS-result patients increased from 9.5% to 16.8%. Patients with ILC had a lower mean RS result than patients with IDC, 16.5 versus 18.4.There is substantial diversity in predicted prognosis among patients with cancers classified as special histologic subtypes, with 12-25% having intermediate RS results and 0.5-9% having high RS results. Pending further definition of the role of chemotherapy for patients with intermediate RS results by TAILORx and RxPONDER, the RS result may help to inform systemic therapy decisions in these patients.

BACKGROUND/OBJECTIVE. Cancers classified as “special histologic subtypes” are felt to have a good prognosis. We used the 21-gene Oncotype DX Breast Recurrence Score® multigene assay to examine prognostic variation within special histologic subtypes. We also examined the Recurrence Score® (RS) distribution among the more common ductal (IDC) and lobular (ILC) cancers. METHODS. 610,350 tumor specimens examined in the Genomic Health clinical laboratory from 2/2004–8/2017 were included. Specimen histology was classified centrally using a single H&E slide and World Health Organization criteria. RS distribution (Low

Multiple synchronous ipsilateral invasive breast carcinomas (BCs) with similar histology usually have concordant receptor status. It is unknown whether individual foci with similar histology also share molecular and biological similarities or are heterogenous. This study examined the concordance of the 21-gene recurrence score (RS) in multiple synchronous morphologically similar ipsilateral BCs. We identified patients with multiple ipsilateral BCs and available RS treated at our institution from 1/2014 to 6/2018. BCs were divided into three groups based on RS: (1) RS in same risk category, (2) RS in different risk categories but within 2-unit difference (e.g., RS 17 and RS 19), and (3) RS in different risk categories and a change of > 2 units. BCs in groups 1 and 2 were considered as concordant (no significant clinical impact) and BCs in group 3 as discordant (variation affects management). A total of 53 patients met the study criteria. RS was concordant in 46 (87%) cases. Seven (13%) cases were discordant (group 3). Of these, three (43%, 3/7) had biopsy cavity changes (BXC) adjacent to the BC with highest RS. In two cases the focus with higher RS had a lower percentage of progesterone receptor-positive tumor cells. In two cases, extensive ductal carcinoma in situ was associated with the BC focus with lower RS. Morphologically similar multifocal ipsilateral BCs have concordant RS in 87% (46/53) of cases. Our results suggest that, in cases of morphologically similar multifocal BCs, testing of a single focus provides accurate prognostic and predictive information.