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The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. These NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of ductal carcinoma in situ and the workup and locoregional management of early stage invasive breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visitNCCN.org.

This publication reviews the current evidence supporting the imaging approach of the axilla in various scenarios with broad differential diagnosis ranging from inflammatory to malignant etiologies. Controversies on the management of axillary adenopathy results in disagreement on the appropriate axillary imaging tests. Ultrasound is often the appropriate initial imaging test in several clinical scenarios. Clinical information (such as age, physical examinations, risk factors) and concurrent complete breast evaluation with mammogram, tomosynthesis, or MRI impact the type of initial imaging test for the axilla. Several impactful clinical trials demonstrated that selected patient's population can received sentinel lymph node biopsy instead of axillary lymph node dissection with similar overall survival, and axillary lymph node dissection is a safe alternative as the nodal staging procedure for clinically node negative patients or even for some node positive patients with limited nodal tumor burden. This approach is not universally accepted, which adversely affect the type of imaging tests considered appropriate for axilla. This document is focused on the initial imaging of the axilla in various scenarios, with the understanding that concurrent or subsequent additional tests may also be performed for the breast. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

The latest version of NCCN Guidelines for Breast Cancer on locoregional management of early-stage breast cancer contains numerous updated recommendations, particularly focusing on management of the axilla, locoregional management after neoadjuvant therapy, and radiation delivery. Recommendations for axillary staging have been separated for patients who have undergone breast-conserving surgery and those who have had a mastectomy, creating 2 individual pathways. The section on locoregional treatment after neoadjuvant therapy has been reformatted; optimal management of this patient group continues to evolve. Lastly, specifics regarding the delivery and sequencing of radiotherapy have been updated.

PDF - 861KB, Marker discovery and validation pipeline.

Supplementary Table 2 from Identification of Breast Cancer DNA Methylation Markers Optimized for Fine-Needle Aspiration Samples

Background: Random periareolar fine-needle aspiration (RP-FNA) is increasingly used in trials of breast cancer prevention for biomarker assessments. DNA methylation markers may have value as surrogate endpoint biomarkers, but this requires identification of biologically relevant markers suitable for paucicellular, lymphocyte-contaminated clinical samples.Methods: Unbiased whole-genome 5-aza-2′-deoxycytidine (5AZA)–induced gene expression assays, followed by several phases of qualitative and quantitative methylation-specific PCR (MSP) testing, were used to identify novel breast cancer DNA methylation markers optimized for clinical FNA samples.Results: The initial 5AZA experiment identified 453 genes whose expression was potentially regulated by promoter region methylation. Informatics filters excluded 273 genes unlikely to yield useful DNA methylation markers. MSP assays were designed for 271 of the remaining genes and, ultimately, 33 genes were identified that were differentially methylated in clinical breast cancer samples, as compared with benign RP-FNA samples, and never methylated in lymphocytes. A subset of these markers was validated by quantitative multiplex MSP in extended clinical sample sets. Using a novel permutation method for analysis of quantitative methylation data, PSAT1, GNE, CPNE8, and CXCL14 were found to correlate strongly with specific clinical and pathologic features of breast cancer. In general, our approach identified markers methylated in a smaller subpopulation of tumor cells than those identified in published methylation array studies.Conclusions: Clinically relevant DNA methylation markers were identified using a 5AZA-induced gene expression approach.Impact: These breast cancer-relevant, FNA-optimized DNA methylation markers may have value as surrogate endpoint biomarkers in RP-FNA studies. Cancer Epidemiol Biomarkers Prev; 22(12); 2212–21. ©2013 AACR.

Supplementary Table 3 from Identification of Breast Cancer DNA Methylation Markers Optimized for Fine-Needle Aspiration Samples

Supplementary Table 1 from Identification of Breast Cancer DNA Methylation Markers Optimized for Fine-Needle Aspiration Samples

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

AimsTouch preparation (TP) and frozen section (FS) are the two methods routinely used in the intraoperative evaluation (IOE) of sentinel lymph nodes (SLNs) to detect metastases in patients with breast cancer. Both methods are extremely sensitive and specific in the primary surgery (non-neoadjuvant systemic therapy (non-NST)) setting. Since NST introduces unique challenges in the IOE of SLNs, the aim was to determine the accuracy of TP and FS in the IOE of SLNs in the NST setting and compare the results with the non-NST setting and to examine factors that contribute to any differences.MethodsWe analysed 871 SLNs from 232 patients (615 SLNs from NST and 256 SLNs from non-NST settings) between 2016 through 2019.ResultsIn the NST group, TP alone (n=366) had a sensitivity of 45.7% and specificity of 99.7%; FS alone (n=90) had a sensitivity of 83.3% and specificity of 100%. When both TP and FS (n=135) were used, the sensitivity was 80.3% and the specificity was 98.6%.In the non-NST group, TP alone (n=193) had a sensitivity of 66.7% and specificity of 100%; FS alone (n=22) had a sensitivity and specificity of 100%; and combined TP and FS (n=34) had a sensitivity and specificity of 100% and 96%, respectively.ConclusionsEvaluating SLNs intraoperatively in the NST setting can be challenging secondary to therapy-related changes. In the NST setting, FS has higher sensitivity and specificity compared with TP for the IOE of SLNs and should be the preferred method.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer-focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor-positive, HER2-negative breast cancer.

A comparative analysis of clinical and pathologic characteristics of HER2 positive breast cancer patients treated with adjuvant versus neoadjuvant antiHer2 therapy: an analysis of 397 cases. Introduction: Currently there are several anti-HER2 therapy options for patients with HER2 positive breast cancer. Surgery as an initial treatment is usually performed in patients with smaller, node negative tumors. Neoadjuvant therapy (NAT) is the treatment of choice for patients with higher stage disease. Detailed analysis of clinical and pathologic characteristics of patients who received adjuvant versus NAT anti-HER2 therapy has not been well elucidated. Objectives: A comparative analysis of clinical and pathologic findings including biomarker expression (ER, PR, HER2 and Ki67) was performed to determine if there were differences in tumor characteristics and clinical outcome in the two groups.Methods:We retrospectively analyzed data on HER2+ breast cancer patients treated with adjuvant and NAT anti-HER2 therapy from 2011 to 2017. Clinical and pathologic parameters including biomarker expression prior to the start of therapy were obtained from the electronic database after IRB approval. In the adjuvant group, patients were treated with initial surgery followed by anti-HER2 therapy plus chemotherapy. In the NAT group, anti-HER2 therapy plus chemotherapy was administered prior to definitive surgery. Types of anti-HER2 therapies and follow-up information were obtained from the electronic medical record. Results:We identified 258 (64.9%) patients who received NAT and 139 (35.0%) received adjuvant anti-HER2 therapy. Table 1.VariablesNeoadjuvant groupAdjuvant groupp-valueAgeBelow 40 years42 (16.2%)11(7.9%)0.02940 years and above Total216 (83.7%) 258128 (92.0%) 139Menopausal statusPremenopausalPostmenopausal Total113 (45.3%)136 (54.6%) 24935 (25.1%)104 (74.8%) 139 Citation Format: Venetia Sarode, Tricia Rood, Yulun Liu, Yisheng Fang, Sunati Sahoo, Yan Peng, Helena Hwang, Marilyn Leitch, Barbara Haley. A comparative analysis of clinical and pathologic characteristics of patients with HER2 positive breast cancer treated with neoadjuvant versus adjuvant anti-HER2 therapy: Analysis of 397 cases [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-02-14.

PURPOSE We report on our early experience of our prospective multicenter phase 1 dose- escalation study of single-fraction stereotactic partial breast irradiation (S-PBI) for early stage breast cancer after partial mastectomy using a robotic stereotactic radiation system. METHODS AND MATERIALS Thirty women with in situ or invasive breast cancer stage 0, I, or II with tumor size

Introduction: The ALTERNATE trial randomized postmenopausal women with ER Allred 6-8 HER2- breast cancer to 6 months of NET with anastrozole (A), fulvestrant (F) or the combination (A+F). Biopsies were taken preNET and after 4-weeks(wks). Patients with Ki67 values >10% at 4-wks were offered triage to neoadjuvant chemotherapy. Patients with on-treatment Ki67 ≤ 10% who completed NET underwent surgery and Ki67 was reassessed. The primary endpoint was endocrine-sensitive disease rate (ESDR). ESD is defined as pCR or PEPI-0 residual disease (pT1-2, pN0, Ki67 ≤ 2.7%). We previously reported that the ESDR difference between the F-containing arms and the A arm was not >10% (ASCO 2020) and that baseline RNA-seq-based intrinsic subtypes predicted outcomes overall (SABCS 2021). Herein we describe relationships between PAM50 intrinsic subtype and Ki67 values by treatment arm because comparative drug effectiveness in adjuvant endocrine therapy studies in ER+ HER2- breast cancer can be predicted by the degree of Ki67 suppression (PMC3518447). Methods: 743 of the 1297 eligible patients (A: 264; F: 231; A+F: 248) had RNA extracted from preNET frozen tumor biopsies with >50% tumor content and subjected to RNA seq. Intrinsic subtypes were then assigned as LumA, LumB, and NonLum (Basal or HER2-E) using open-source PAM50-based informatics. Differences in the proportion with wk4 Ki67 > 10%, % change in wk4 ki67, and surgical CCCA (Ki67 ≤ 2.7%) rate (sxCCCA) between treatments and by intrinsic subtype was assessed using stratified logistic regression, Wilcoxon rank sum test, and Fisher’s exact test, respectively. Analysis of sxCCCA excluded those who failed to complete NET for reasons other than disease progression or early Ki67 >10%. Results: Amongst the 358 LumA cases there were no significant differences in Ki67-based endpoints between treatments. Among the 292 LumB cases, the wk4 ki67 > 10% rate was lower with A+F (19.4%) than A (43%) (P=0.0002) and was somewhat lower in F (31%) versus A (P=0.076). The % change in wk4 Ki67 in LumB cases, adjusted for baseline Ki67, showed markedly superior suppression for A+F versus A (-90% vs. -77%; P= Conclusion: The combination of A+F was significantly more effective than either drug alone for the control of LumB breast cancer cell proliferation. This suggests that A+F may be a more effective adjuvant endocrine therapy than A alone in LumB disease. The lower Ki67 suppression with A alone also suggests that poorer outcome in some LumB tumors may be due to insufficient ER targeting rather than ER-independent tumor growth Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG), NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org. (MJE) CPRIT RR140033, P50-CA186784, P50-CA58223, U01-CA214125, U24-CA210954, Gift from Ralph and Lisa Eads, McNair Scholarship. ClinicalTrials.gov Identifier: NCT01953588 Citation Format: Matthew J. Ellis, Meenakshi Anurag, Jeremy Hoog, Aranzazu Fernandez-Martinez, Cheng Fan, Richard Gibbs, Souzan Sanati, Kiran Vij, Mark Watson, Travis Dockter, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erica Crouch, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J. Hieken, Yang Wang, A. Marilyn Leitch, Gary W. Unzeitig, Eric Winer, Anna Weiss, Kelly Hunt, Ann H. Partridge, Charles M. Perou, Vera Suman, Cynthia X. Ma, Lisa A. Carey. The effect of intrinsic subtype on inhibition of tumor growth by anastrozole vs. fulvestrant vs. the combination: Results from the Alliance neoadjuvant endocrine therapy (NET) ALTERNATE trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT026.

Our purpose was to evaluate cosmetic changes after 5-fraction adjuvant stereotactic partial breast irradiation (S-PBI).Seventy-five women with in situ or invasive breast cancer stage 0, I, or II, with tumor size ≤3 cm, were enrolled after lumpectomy in a phase 1 dose escalation trial of S-PBI into cohorts receiving 30, 32.5, 35, 37.5, or 40 Gy in 5 fractions. Before S-PBI, 3 to 4 gold fiducial markers were placed in the lumpectomy cavity for tracking with the Synchrony respiratory tracking system. S-PBI was delivered with a CyberKnife robotic radiosurgery system. Patients and physicians evaluated global cosmesis using the Harvard Breast Cosmesis Scale. Eight independent panelists evaluated digital photography for global cosmesis and 10 subdomains at baseline and follow-up. McNemar tests were used to evaluate change in cosmesis, graded as excellent/good or fair/poor, from baseline to year 3. Wilcoxon signed rank tests were used to evaluate change in subdomains. Cohen's kappa (κ) statistic was used to estimate interobserver agreement (IOA) between raters, and Fleiss' κ was used to estimate IOA between panelists.Median cosmetic follow-up was 5, 5, 5, 4, and 3 years for the 30, 32.5, 35, 37.5, and 40 Gy cohorts. Most patients reported excellent/good cosmesis at both baseline (86.3%) and year 3 (89.8%). No dose cohort had significantly worsened cosmesis by year 3 on McNemar analysis. No cosmetic subdomain had significant worsening by year 3. IOA was fair for patient-physician (κ = 0.300, P.001), patient-panel (κ = 0.295, P.001), physician-panel (κ = 0.256, P.001), and individual panelists (Fleiss κ = 0.327, P.001).Dose escalation of S-PBI from 30 to 40 Gy in 5 fractions for early stage breast cancer was not associated with a detectable change in cosmesis by year 3. S-PBI is a promising modality for treatment of early stage breast cancer.

This study reports predictive dosimetric and physiologic factors for fat necrosis after stereotactic-partial breast irradiation (S-PBI).Seventy-five patients with ductal carcinoma-in situ or invasive nonlobular epithelial histologies stage 0, I, or II, with tumor size3 cm were enrolled in a dose-escalation, phase I S-PBI trial between January 2011 and July 2015. Fat necrosis was evaluated clinically at each follow-up. Treatment data were extracted from the Multiplan Treatment Planning System (Cyberknife, Accuray). Univariate and stepwise logistic regression analyses were conducted to identify factors associated with palpable fat necrosis.With a median follow-up of 61 months (range: 4.3-99.5 months), 11 patients experienced palpable fat necrosis, 5 cases of which were painful. The median time to development of fat necrosis was 12.7 months (range, 3-42 months). On univariate analyses, higher V32.5-47.5 Gy (P.05) and larger breast volume (P.01) were predictive of any fat necrosis; higher V35-50 Gy (P.05), receiving 2 treatments on consecutive days (P = .02), and higher Dmax (P = .01) were predictive of painful fat necrosis. On multivariate analyses, breast volume larger than 1063 cmEarly-stage breast cancer patients treated with breast conserving surgery and S-PBI in our study had a fat necrosis rate comparable to other accelerated partial breast irradiation modalities, but S-PBI is less invasive. To reduce risk of painful fat necrosis, we recommend not delivering fractions on consecutive days; limiting V42.550 cm

Background: Neoadjuvant ET (NET) offers an opportunity to assess ET sensitivity for ER+ HER2- BC and potentially to tailor therapy. Ki67 >10% on biopsy after 2-4 weeks (wks) of NET identifies patients (pts) with intrinsic ET resistance; while pathologic complete response (pCR) and modified preoperative endocrine prognostic index of 0 (mPEPI 0: pT1-2N0, Ki67 ≤2.7%) at surgery indicates sensitivity to ET. However, on-NET biopsy is not always acceptable or feasible and delays the ET sensitivity determination. PAM50 ROR score and intrinsic subtypes by tumor RNA profiling are prognostic in pts with early stage ER+ HER2- BC, and predict pCR rates to neoadjuvant chemotherapy (NCT) (PMC2667820). We therefore hypothesized that PAM50 analysis on pre-NET biopsies could predict the likelihood of a) a high on-NET Ki67, b) mPEPI-0 or pCR at surgery and, c) pCR for pts triaged to NCT. Methods: The ALTERNATE trial is a phase III study that randomized postmenopausal pts with clinical stage II/III ER+ (Allred score 6-8) HER2- BC to receive neoadjuvant anastrozole, fulvestrant, or both for 6 months before surgery. Research biopsy was required at pre-NET and wk 4, then optional at wk 12. Pts with Ki67 >10% on biopsy at wk 4 or 12 discontinued NET and were offered NCT. PAM50 intrinsic subtype and ROR-P values were generated from mRNA sequencing (RNASeq) analysis on pre-NET biopsies using open-source informatics (PMC7723687) and evaluated for prediction of on-NET Ki67 >10% at wk 4 or 12, pCR or mPEPI-0 post NET, and pCR post NCT. Results: 749 of 1,297 eligible trial pts were included in the analyses, after excluding 548 pts due to insufficient pre-NET tumor for RNASeq (n=511) or PAM50 normal subtype (n=37). Similar to the entire ALTERNATE population, the rate of Ki67 >10% at wk 4 or 12 was 24.4% (95% CI: 21.4-27.7%) and the rate of mPEPI-0/pCR post NET was 19.8% (95% CI: 17.0-22.8%). There were 393 (52.5%) Lum A, 302 (40.3%) Lum B, and 54 (7.2%) non-Lum (9 Basal, 45 HER2-E) BCs. These included 196 (26.2%) ROR-P low, 354 (47.3%) ROR-P medium and 199 (26.6%) ROR-P high BCs. Both the rates of Ki67 >10% at wk 4 or 12 and mPEPI-0/pCR differed significantly with respect to PAM50 subtype or ROR-P category, such that Lum A or ROR-P low BCs were least likely to have a Ki67 >10% at wk 4 or 12 and most likely to achieve mPEPI-0/pCR (Table). 93 of 168 (55.4%) pts triaged to NCT had RNA-seq results, yielding 26 Lum A, 49 Lum B, 4 Basal and 14 HER2-E, with the pCR rates of 0%, 6.1%, 0%, and 21.4%, respectively. There were 10 ROR-P low, 39 medium, and 44 high tumors, with a pCR rate of 0%, 5.1% and 9.1%, respectively. Conclusion: These data indicate that both baseline ROR-P and intrinsic subtype are predictive of early on-NET Ki67 > 10% and mPEPI 0/pCR at surgery after NET. For pts triaged to NCT based on an early on-NET Ki67 >10%, the HER2-E group had the highest pCR rate (20%) and no pCRs were observed in Lum A. These data may be useful for directing neoadjuvant therapy in postmenopausal pts with ER+ HER2- BC. Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG), NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org. (MJE) CPRIT RR140033, P50CA186784, P50-CA58223, U01 CA214125, U24CA210954, Gift from Ralph and Lisa Eads, McNair Scholarship. Trials.gov Identifier: NCT01953588. Table 1.Rates of Ki67 >10% and mPEPI-0/pCR post NET by PAM50 subtype and ROR-P categoryKi67 >10% at wk 4 or 12mPEPI 0/pCR post NETPAM50 SubtypenYes, n (%)PnNo, n (%)PLum A37251 (13.7%) 95% CI: 10.4-17.6% Citation Format: Cynthia X Ma, Meenakshi Anurag, Travis Dockter, Jeremy Hoog, Aranzazu Fernandez-Martinez, Cheng Fan, Richard Gibbs, Souzan Sanati, Kiran Vij, Mark Watson, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erika Crouch, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J Hieken, Yang Wang, A. Marilyn Leitch, Gary W Unzeitig, Anna Weiss, Eric P Winer, Kelly Hunt, Ann H Partridge, Lisa A Carey, Charles M Perou, Matthew J Ellis, Vera Suman. Pam50 intrinsic subtype and risk of recurrence score (ROR) for the prediction of endocrine (ET) sensitivity and pathologic response to chemotherapy in postmenopausal women with clinical stage II/III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) in the alternate trial (Alliance A011106) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD9-03.

Background Breast cancer metastases to an ipsilateral supraclavicular lymph node is assigned a N3 status in the TNM system and thus classified as stage III disease in the American Joint Commission on Cancer staging manual. Breast cancer metastatic to contralateral axillary lymph node (CAM) without metastases to any other distant organ is currently assigned M1 status (stage IV) instead of N3 (stage III). Patients and Methods We retrospectively reviewed the medical records of breast cancer patients diagnosed with CAM for their clinical presentation, pathologic diagnoses, treatment, and follow-up data. Patients who had distant metastases at the time of CAM diagnosis were excluded from the study. Results We report 12 breast cancer patients who developed CAM but no evidence of metastases in any other distant organ documented with extensive imaging workup. Imaging studies and thorough pathologic evaluation of the prophylactic total mastectomy specimen did not reveal a primary in the breast to account for the metastases in the axillary node. Conclusion Findings of our study as well as previous studies support that lymph node metastases in the contralateral axilla represents a locoregional spread of the tumor from the index breast via lymphatics rather than hematogenous spread. Therefore, isolated CAM in breast cancer patients should not be classified as stage IV disease.

PURPOSE/OBJECTIVE(S) We report on our early experience of a phase I dose escalation study of single fraction stereotactic partial breast irradiation (S-PBI) for early-stage breast cancer after partial mastectomy using a robotic stereotactic radiation system. MATERIALS/METHODS Patient eligibility included DCIS or invasive epithelial histologies, AJCC clinical stage 0, I, or II with tumor size < 3 cm, and negative margins. Prior to simulation, 3-4 gold fiducials were placed around the lumpectomy cavity to be used for real-time tracking during treatments. Dose limiting toxicity (DLT) was defined as grade ≥ 3 toxicity by CTCAE (version 4) deemed definitely related to treatment for: skin, ribs/bone (fracture), pulmonary (radiation pneumonitis), or neurological (intercostal or brachial plexus nerves) or any grade 4 or 5 toxicity definitely attributed to therapy. Both patients and physicians completed baseline and subsequent cosmesis outcome questionnaires using a 4-point scale ranging from excellent, good, fair, or poor. Cohort 1 was 22.5 Gy, cohort 2 26.5 Gy, and cohort 3 30 Gy all delivered in a single fraction. Dose escalation was permitted provided that one or fewer of the first seven, or two or fewer of nine patients experienced a DLT within 90 days of treatment within each dose group. If more patients had DLT in a given dose cohort, the maximum tolerable dose (MTD) would have been exceeded. RESULTS From 4/2016 to 1/2021, 11, 9, and 10 patients were treated on cohorts 1, 2 and 3 respectively. Of these, data from 18 evaluable patients from cohorts 1 and 2 and 6 patients from cohort 3, with at least 12 months of follow up are reported. Median f/u for cohort 1 was 36 m (r 24-48m), cohort 2 was 18 m (r 18-24m), and cohort 3 12 m (r 1-18m). Average age was 66.8 (r 47-84). Histology included 11 DCIS, and 19 invasive carcinomas. Of 11 DCIS, 9 were ER+, and 2 were ER-. All 19 invasive tumors were ER+. 23/29 patients received endocrine therapy, and no patient received chemotherapy. No patients experienced grade 3 or higher treatment related toxicity in the acute period (≤ 90 days), and MTD was not reached. There were two delayed grade 3 toxicities, (dose cohort 1 and 2, one patient had breast pain, and another had mastitis at 12 months and 9 months). No patients experienced grade 4 or 5 toxic events. Five patients developed fat necrosis in all three cohorts. Physicians scored cosmesis excellent or good at last follow-up in (10/11) 90%, (7/8) 87.5%, and (6/6)100%, in cohort 1,2, and 3 respectively, while patients scored excellent or good in (11/11) 100%, 8/8 (100%), and 5/6 (83%) patients. There has been no report of disease recurrences. CONCLUSION Dose was escalated to 30 Gy in single fraction, and the majority of patients maintained good or excellent cosmetic outcome, without grade 3 or 4 toxicity. Continued analysis of all cohorts are in progress.

Background: Ki67 values >10% 2-4 weeks (wks) after starting neoadjuvant ET (NET) indicates persistent cell proliferation, resistance to ET, and is associated with increased risk of recurrence. The ACOSOG Z1031 trial suggested that these tumors are also relatively chemotherapy (chemo) resistant with a low pathologic complete response (pCR) rate to NCT. The ALTERNATE trial (NCT01953588) is a randomized study of neoadjuvant anastrozole (ANA), fulvestrant (FUL), or ANA + FUL in postmenopausal patients (pt) with newly diagnosed clinical stage II or III ER+ (Allred score 6-8)/HER2- BC. Ki67 >10% at wk 4 or 12 after starting NET triggered triage to NCT of physician choice or weekly paclitaxel. Pts who refused protocol-directed therapy, were not candidates for NCT, or decided to undergo immediate surgery are being followed per protocol. Here we report the rates of pCR and residual cancer burden (RCB) following NCT for pts triaged to NCT due to Ki67 >10% at wk 4 or 12. Results: Of the 1,299 eligible pts randomized to receive ANA, FUL, or ANA + FUL, 286 (22%) had Ki67 >10% at wk 4 or 12. 168 of these 286 pts (58.7%) chose to switch to NCT, 32 went to surgery (11.2%), and 86 discontinued further protocol-directed therapy (30.1%). Among the 168 pts who underwent NCT, the presenting clinical T stages were cT2 (n=113; 67.26%), cT3 (n=47; 27.98%) and cT4 (n=8; 4.76%) and N stages were cN0 (n=82; 48.8%), cN1 (n=75; 44.6%), cN2/3 (n=9; 5.4%) and cNx (n=2; 1.2%). Central ER testing was performed on pre-treatment biopsies and confirmed ER Allred score 6-8 in 155 of 168 (92.2%) pts, with the rest being ER Allred score 4-5 (n=5; 3%), ER- (Allred score 0) (n=2; 1.2%), or not tested (n=6; 3.6%). Most (n=139; 82.7%) were ER+/PR+, while 17.3% (n=29) were ER+/PR-, and tumor grades were G1 (n=10; 6%), G2 (n=99; 58.9%), G3 (n=54; 32.1%), not reported (n=5; 3%). Baseline Ki67 levels prior to NET were >10% in 94% (n=158), ≤10% in 3% (n=5), and not done in 3% (n=5). NCT regimens administered included doxorubicin/cyclophosphamide (AC) followed by paclitaxel (T) (n=60; 35.71%); weekly paclitaxel (n=56; 33.33%), docetaxel/cyclophosphamide (TC) (n=33; 19.65%), other doxorubicin and/or taxane containing regimen (n=17; 10.12%), and cyclophosphamide/methotrexate/fluorouracil (CMF) (n=2; 1.19%). 35 (20.8%) pts did not complete planned course of NCT due to toxicity (n=27) or refusal (n=8). 154 NCT pts underwent surgery (mastectomy in 40.3%, and breast conserving surgery in 59.7%). The path ypT stages were Tis/0 (n=10; 6.5%), T1 (n=62; 40.3%), T2 (n=61; 39.6%), and T3/4 (n=21; 13.6%), and the ypN stages were N0 (n=66; 42.9%), N1 (n=57; 37%), N2/3 (n=30; 19.5%), and Nx (n=1; 0.6%). Among the 168 pts who started on NCT (intent to treat population), there were 8 pCRs (no invasive disease in the breast or lymph nodes) (4.8%; 95% CI: 2.1% to 9.2%). Residual Cancer Burden (RCB) categories include RCB 0 (n=8; 4.8%), RCB 1 (n=15; 8.9%), RCB 2 (n=82; 48.8%), RCB 3 (n=42; 25.0%), and not determined (n=21; 12.5%). Correlations of baseline pt and tumor characteristics with pathology response to NCT will also be presented. Conclusion: In pts with NET-resistant ER+/HER2- BC, salvage NCT is not likely to induce a complete or near complete response. More effective treatments are needed for this high-risk ER+/HER2- pt population. Support: U10CA180821, U10CA180882, U24CA196171, UG1CA189856, U10CA180868 (NRG); NCI BIQSFP, BCRF, Genentech, AstraZeneca. https://acknowledgments.alliancefound.org. Clinical Trials.gov Identifier: NCT01953588 Citation Format: Cynthia X Ma, Vera Suman, A. Marilyn Leitch, Souzan Sanati, Kiran Vij, Gary W Unzeitig, Jeremy Hoog, Mark Watson, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erika Crouch, Horacio Maluf, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J Hieken, Yang Wang, Travis Dockter, Jo Anne Zujewski, Anna Weiss, Kelly Hunt, Clifford Hudis, Eric P Winer, Matthew J Ellis, Lisa A Carey, Ann H Partridge. Neoadjuvant chemotherapy (NCT) response in postmenopausal women with clinical stage II or III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) resistant to endocrine therapy (ET) in the ALTERNATE trial (Alliance A011106) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-05.

Intraoperative specimen radiographs performed during breast conservation surgery for cancer reduces the need for re-excision for positive margins. We studied 2D versus 3D image-guided cavity margin excision and compared it to final pathology and need for additional surgery. We conducted a retrospective review of 657 breast-conserving operations performed for cancer from 2013 to 2018. Procedures were performed by four surgeons at a single tertiary institution with access intraoperatively to 2D and 3D radiographs. Data collected included demographics, intraoperative margin assessment, final pathology, and re-excision rates. A total of 466 patients had 2D and 191 had 3D specimen imaging. The 2D group had a lower mean age and a higher body mass index and proportion of minority patients than the 3D group (P < 0.01). In the 3D group, there was a higher percentage of patients with mammographically denser breasts (P < 0.06); 58% of patients in the 3D group had additional imaging-directed cavity margins excised versus 32% of patients in the 2D group (P < 0.01). In the 2D group, 44 patients (9%) had positive final margins versus 8 patients (4%) in the 3D group (P = 0.02). No difference was found on total volume of excision (P = 0.56). The re-excision rate for the 2D group was 11% versus 5% for the 3D group (P = 0.02; adjusted odds ratio = 0.41, 95% confidence interval 0.19–0.86). Re-excision rates using both modalities are low. A lower re-excision rate is independently associated with 3D tomosynthesis. This allows surgeons to excise additional margins at the index operation, decreasing reoperations and anxiety/costs for patients.

We conducted a randomized, double-blind, vehicle-controlled clinical trial to investigate the use of a new proprietary hyaluronan (HA) formulation for the prevention of acute skin toxicity in breast cancer patients undergoing radiotherapy (RT). Thirty women with breast cancer undergoing whole breast RT were enrolled. Each patient was randomly assigned to HA formulation (study cream, S) on the medial or lateral half of the irradiated breast and the control cream (placebo, P) on the other half. The primary endpoint was physician’s evaluation of skin symptoms at week 5 during RT and week 2 post-RT. We also collected patients’ independent assessment of skin after RT, patient’s product preference, and an independent physician panel assessment of skin reactions based on photographs. Twenty-eight patients were evaluable. On physician’s evaluation, there was no significant difference in radiation dermatitis between S and P and no overall preference to either cream at week 5 during or week 2 post-RT. More patients preferred S in evaluating skin appearance and skin reactions, but this did not reach statistical significance. Univariate analysis showed that physicians had an overall preference to the S cream at week 2 post-RT in patients with larger breasts. On the independent panel assessment, 3 reviewers saw no significant difference in radiation toxicity, whereas one reviewer reported better skin outcome with S cream at week 5. We found a nonstatistically significant patient preference but overall no significant radioprotective effects for this HA formulation compared with placebo except in patients with larger breasts. The study was registered at www.clinicaltrials.gov (NCT02165605).

The objective is to define the therapeutic role of antiplatelet agents in a triple-negative breast cancer (TNBC) population. We performed retrospective analysis using the UTSW TNBC registry containing data from 222 Stage II–III TNBC patients treated between 1998 and 2016. Univariate analysis and multivariable logistic regression models were constructed to identify factors associated with disease-free survival (DFS), distant metastases rate (DMR), and overall survival outcomes. Antiplatelet drug use was determined by review of electronic medical records. A total of 65 patients used antiplatelet (AP) agents, and 157 patients did not use AP agents. Median follow-up for AP and non-AP groups was 41.3 and 40.9 months, respectively. There was an improvement in the AP group compared with the control group in 5-year DFS (80.4% at 5 years compared with 62.3% in the control group, p = 0.04) and 5-year DMR (8.8 vs. 31.9%, p = 0.007). In multivariate analysis, AP use was found to be significantly associated with improvements in DFS and DMR. We illustrate that antiplatelet agent use improves DMR and DFS among a stage II and III TNBC population despite our short follow-up evaluation. Longer follow-up evaluation will be required to determine additional outcome advantage for antiplatelet agent use. Our findings support consideration of investigation of antiplatelet therapy as an adjunctive therapy for TNBC at high risk for disease recurrence.

BACKGROUND Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2)/neu receptors, and is aggressive and therapeutically challenging. Genetic ancestry testing is an emerging medical field. Mitochondrial DNA (mtDNA), which is distinct from nuclear DNA, is maternally inherited and allows for origin determination. Patients with TNBC tend to be younger and are more likely to be African American, making this an ideal disease for mtDNA exploration. To the authors' knowledge, the current study is the first to perform mtDNA for self-described African American, White, and Hispanic patients with TNBC to identify mtDNA patterns. METHODS Patients with TNBC who were at any stage of therapy/survivorship were included. Self-reported ethnicity was confirmed at the time of the prospective buccal swab. Haplogroup prediction was performed on sequencing of hypervariable region 1. Using sequence similarity scores and lineage databases, sequence patterns were determined. Data regarding presentation and treatment, tumor features, and outcomes was collected. RESULTS A total of 92 patients were included: 31 self-described African American, 31 White, and 30 Hispanic individuals. Hispanic patients were found to have the largest tumor size (4.5 cm; P = .01) and youngest age (41 years; P

504 Background: For PM patients (pts) with locally advanced ER+ HER2- BC, NET improves breast conservation surgery (BCS) rates, and modified preoperative endocrine prognostic index (mPEPI) 0, defined as pT1-2 pN0 Ki67< 2.7%, or pathologic complete response (pCR: no invasive disease in breast or lymph node) is associated with low risk of recurrence without adjuvant chemotherapy (CT). The ALTERNATE trial was initiated to assess if the endocrine-sensitive disease rate (ESDR: number of mPEPI 0 pts/number of eligible pts initiating NET) with fulvestrant (F) or F+anastrozole (A) is improved relative to A alone (reported here) and if the 5-year (yr) recurrence-free survival (RFS) rate for pts with mPEPI 0 on A alone without CT is ≥ 95% (awaits further follow-up). Methods: PM pts with clinical stage II/III ER+ HER2- BC were randomized 1:1:1 to 1 mg A po daily, 500 mg F IM every 4 week (wk)s after loading dose, or A+F for 6 months. Ki67 was tested centrally on biopsies acquired prior to NET, wk 4, wk 12 and at surgery. Pts with Ki67 >10% at wk 4 or 12 were recommended to go off protocol-directed ET and switch to CT. Pts with mPEPI 0 at surgery were recommended to continue assigned ET for 1.5 yrs followed by A for a total of 5 yrs ET (and not to receive CT). The primary endpoint of the neoadjuvant phase was ESDR. ESDR of each F arm was compared to that of the A alone arm. With 425 pts per arm, a one-tailed alpha = 0.025 chi-square test of two independent proportions has 84% power to detect an increase of ≥10% in ESDR for F or F+A compared to the A arm, assuming ESDR ≤30% in A. Results: 1362 pts (A 452; F 454; A+F 456) were enrolled Feb 2014 to Nov 2018. 63 pts were excluded (did not start NET). Of the remaining 1299 pts (A 434; F 431, A+F 434), 42% were cN1-3 and 73% were considered candidates for BCS. ESDR was 18.6% (95%CI: 15.1-22.7%) with A, 22.7% (95%CI: 18.9-27.0%) with F, and 20.5% (95%CI: 16.8-24.6%) with A+F. No significant difference in ESDR was found between A and F (p=0.15) or A and A+F (p=0.55). Among the 825 pts with wk 4 Ki67 < 10% who completed NET and surgery, ESDR and the BCS rate were 27.7% and 70.3% with A; 29.6% and 68.1% with F, and 26.8% and 69.9% with A+F, respectively. Conclusion: Neither F nor F+A significantly improved ESDR compared to A alone in PM pts with locally advanced ER+ HER2- BC. RFS data are awaited. Support: U10CA180821, U10CA180882, U24CA196171, https://acknowledgments.alliancefound.org ; NCI BIQSFP, BCRF, Genentech, AstraZeneca. Clinical trial information: NCT01953588 .

Solid cancer cells commonly enter the blood and disseminate systemically, but are highly inefficient at forming distant metastases for poorly understood reasons. Here we studied human melanomas that differed in their metastasis histories in patients and in their capacity to metastasize in NOD-SCID-Il2rg(-/-) (NSG) mice. We show that melanomas had high frequencies of cells that formed subcutaneous tumours, but much lower percentages of cells that formed tumours after intravenous or intrasplenic transplantation, particularly among inefficiently metastasizing melanomas. Melanoma cells in the blood and visceral organs experienced oxidative stress not observed in established subcutaneous tumours. Successfully metastasizing melanomas underwent reversible metabolic changes during metastasis that increased their capacity to withstand oxidative stress, including increased dependence on NADPH-generating enzymes in the folate pathway. Antioxidants promoted distant metastasis in NSG mice. Folate pathway inhibition using low-dose methotrexate, ALDH1L2 knockdown, or MTHFD1 knockdown inhibited distant metastasis without significantly affecting the growth of subcutaneous tumours in the same mice. Oxidative stress thus limits distant metastasis by melanoma cells in vivo.

Background: The Preoperative Endocrine Prognostic Index (PEPI) is a method to predict outcome after neoadjuvant endocrine therapy that integrates Ki67, estrogen receptor (ER) analysis and pathological stage from the surgical specimen (Ellis, JNCI 100:1380, 2008). We sought to further develop the PEPI for use in clinical trials by: a) establishing an efficient SOP for Ki67 analysis, b) determining the effect of simplifying the score by removing the ER component (modified "mPEPI") and c) independent validation of mPEPI in the ACOSOG (Alliance) Z1031 neoadjuvant aromatase inhibitor trial (Ellis, M, JCO 29:234, 2011). Methods: Ki-67 assay development focused on reproducing a 2.7% Ki-67 cut point (CP) required for PEPI. Ventana Image analysis (IA) to replace labor-intensive visual point counting (VPC) was assessed to increase scoring efficiency. Discordant scores led to a triage approach where cases with complex histological features that could not be resolved by IA were flagged for VPC. The Ki-67 scoring approach was preliminarily validated on T1/2 N0 cases from the P024 and POL trials (SABCS 2013, abstract P3-05-190). Models with and without ER suggested ER was dispensable. A locked SOP for mPEPI was subsequently applied to the Z1031A trial. The primary endpoint was time from the date of surgery to local, regional, or distant recurrence in the mPEPI-0 group (T1/2 N0, Ki67 0 group. Results. mPEPI by IA was evaluated on 202 of 377 (53%) patients enrolled into Z1031A (6% of IA results were triaged to VPC). All patients have been followed a minimum of 2 years (median: 5 years; max: 7 years). Only 10 patients in the mPEPI-0 group (22.7%) received adjuvant chemotherapy, versus 78 in the mPEPI>0 group (49.4%). Time to breast cancer recurrence was decreased among those with mPEPI>0 status relative to those with mPEPI-0 status (log rank p=0.012). Only one disease event among 44 (2%) cases with mPEPI-0 was observed versus 26 of 158 cases with mPEPI>0 (16.5%) Conclusions. mPEPI-0 status can identify patients at low risk of relapse after neoadjuvant endocrine therapy: therefore mPEPI-0 status has operational characteristics similar to pCR after chemotherapy for ER-negative disease. mPEPI is undergoing prospective validation in the Alliance ALTERNATE trial that will assess whether Fulvestrant increases the mPEPI-0 rate and also will prospectively determine whether patients with mPEPI-0 status can safely be managed without adjuvant chemotherapy treatment. Citation Format: Souzan Sanati, Vera J Suman, Rodrigo Goncalves, Katherine DeSchryver, Cynthia X Ma, Jeremy Hoog, Erika Crouch, Michael Barnes, Gary Unzeitig, A Marilyn Leitch, Kelly K Hunt, Matthew J Ellis. Validation of the preoperative endocrine prognostic index in the ACOSOG (Alliance) Z1031 neoadjuvant aromatase inhibitor trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-13.

Background Obesity and high radiologic breast density independently increase breast cancer risk. We evaluated the effect of surgical weight loss on mammographic density (MD). Methods Patients undergoing bariatric surgery and screening mammography (MG) were identified, data regarding demographics, comorbidities, calculated and genetic breast cancer risk was collected. Patients had a MG before and after surgery. Fellowship-trained breast radiologists assigned Breast Imaging Reporting and Data System density categories. Results Patients underwent sleeve gastrectomy (n = 56) or gastric bypass (n = 7), 78% had hypertension, 48% had diabetes. Four had deleterious BRCA mutations, four were calculated high risk. Mean weight loss = 28.7 kg. Mean initial BMI = 44.3 kg/m2 (range:33–77), final BMI = 33.6 kg/m2 (range:20–62;p

Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).

Background: Random periareolar fine-needle aspiration (RP-FNA) is increasingly used in trials of breast cancer prevention for biomarker assessments. DNA methylation markers may have value as surrogate endpoint biomarkers, but this requires identification of biologically relevant markers suitable for paucicellular, lymphocyte-contaminated clinical samples. Methods: Unbiased whole-genome 5-aza-2′-deoxycytidine (5AZA)–induced gene expression assays, followed by several phases of qualitative and quantitative methylation-specific PCR (MSP) testing, were used to identify novel breast cancer DNA methylation markers optimized for clinical FNA samples. Results: The initial 5AZA experiment identified 453 genes whose expression was potentially regulated by promoter region methylation. Informatics filters excluded 273 genes unlikely to yield useful DNA methylation markers. MSP assays were designed for 271 of the remaining genes and, ultimately, 33 genes were identified that were differentially methylated in clinical breast cancer samples, as compared with benign RP-FNA samples, and never methylated in lymphocytes. A subset of these markers was validated by quantitative multiplex MSP in extended clinical sample sets. Using a novel permutation method for analysis of quantitative methylation data, PSAT1, GNE, CPNE8, and CXCL14 were found to correlate strongly with specific clinical and pathologic features of breast cancer. In general, our approach identified markers methylated in a smaller subpopulation of tumor cells than those identified in published methylation array studies. Conclusions: Clinically relevant DNA methylation markers were identified using a 5AZA-induced gene expression approach. Impact: These breast cancer-relevant, FNA-optimized DNA methylation markers may have value as surrogate endpoint biomarkers in RP-FNA studies. Cancer Epidemiol Biomarkers Prev; 22(12); 2212–21. ©2013 AACR.

Multiple localizers placed in a bracketed fashion facilitates excision of radiographically extensive breast lesions. In this study, bracketed radioactive seed localization (bRSL) was compared to bracketed wire localization (bWL). We hypothesized that bRSL would achieve adequate margins and decrease re-operation rates with similar or less specimen volumes (SV) than bWL. Retrospective review identified patients who underwent bracketed breast procedures at an academic medical center. Data collected included patient demographics, tumor features, treatment variables, and surgical outcomes. Wilcoxon rank-sum test and chi-square test were used to compare continuous and categorical data, respectively. A multivariable logistic regression model was used to evaluate the association between re-excision and localization technique after adjusting for clinically relevant variables. Patients who underwent bWL were 3.9 times more likely to undergo re-excision compared to patients in bRSL group (OR=3.9, 95% CI: 2.0-7.4). Initial and total SV did not significantly differ between the two groups (P=.4). Patients were significantly more likely to undergo a mastectomy in the bWL group than in the bRSL group (24% vs 7%; P

The early results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial demonstrated no difference in locoregional recurrence for patients with positive sentinel lymph nodes (SLNs) randomized either to axillary lymph node dissection (ALND) or sentinel lymph node dissection (SLND) alone. We now report long-term locoregional recurrence results.ACOSOG Z0011 prospectively examined overall survival of patients with SLN metastases undergoing breast-conserving therapy randomized to undergo ALND after SLND or no further axillary specific treatment. Locoregional recurrence was prospectively evaluated and compared between the groups.Four hundred forty-six patients were randomized to SLND alone and 445 to SLND and ALND. Both groups were similar with respect to age, Bloom-Richardson score, Estrogen Receptor status, adjuvant systemic therapy, histology, and tumor size. Patients randomized to ALND had a median of 17 axillary nodes removed compared with a median of only 2 SLNs removed with SLND alone (P0.001). ALND, as expected, also removed more positive lymph nodes (P0.001). At a median follow-up of 9.25 years, there was no statistically significant difference in local recurrence-free survival (P = 0.13). The cumulative incidence of nodal recurrences at 10 years was 0.5% in the ALND arm and 1.5% in the SLND alone arm (P = 0.28). Ten-year cumulative locoregional recurrence was 6.2% with ALND and 5.3% with SLND alone (P = 0.36).Despite the potential for residual axillary disease after SLND, SLND without ALND offers excellent regional control for selected patients with early metastatic breast cancer treated with breast-conserving therapy and adjuvant systemic therapy.

Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2)/neu receptors, and is aggressive and therapeutically challenging. Genetic ancestry testing is an emerging medical field. Mitochondrial DNA (mtDNA), which is distinct from nuclear DNA, is maternally inherited and allows for origin determination. Patients with TNBC tend to be younger and are more likely to be African American, making this an ideal disease for mtDNA exploration. To the authors' knowledge, the current study is the first to perform mtDNA for self-described African American, White, and Hispanic patients with TNBC to identify mtDNA patterns.Patients with TNBC who were at any stage of therapy/survivorship were included. Self-reported ethnicity was confirmed at the time of the prospective buccal swab. Haplogroup prediction was performed on sequencing of hypervariable region 1. Using sequence similarity scores and lineage databases, sequence patterns were determined. Data regarding presentation and treatment, tumor features, and outcomes was collected.A total of 92 patients were included: 31 self-described African American, 31 White, and 30 Hispanic individuals. Hispanic patients were found to have the largest tumor size (4.5 cm; P = .01) and youngest age (41 years; P.0001). Eight patients were BRCA1/2 mutation carriers. There were no differences noted among groups with regard to surgery, lymph node metastases, or survival. Analysis revealed Nigerian, Cameroon, or Sierra Leone ancestry and haplogroups A, U, H, or B to be the most common mtDNA patterns. Twelve discordances (13%) between mtDNA analysis and self-described ethnicity were identified among the 92 patients. The highest discordance (26%; 8 patients) was noted in self-described Hispanic patients: 3 had Nigerian ancestry, and 1 individual demonstrated haplogroup K mtDNA (Ashkenazi Jewish ancestry).Discordance between self-reported ethnicity and mtDNA analysis was identified in 13% of patients with TNBC. The identification of mtDNA patterns with a predisposition toward TNBC may allow for risk stratification. Cancer 2017;107-113. © 2016 American Cancer Society.

Background: Accurate assessment of HER2 status is critical for selecting patients who will benefit from trastuzumab therapy. There is still no consensus regarding the optimal method to assess HER2 status. Computerized image analysis has been shown to provide a more accurate and objective way for quantification of HER2 expression by IHC than manual evaluation. It has been suggested that the use of image analysis may help to resolve some of the discrepancies between IHC and FISH assay. We compared the results of HER2 expression by IHC using automated image analysis with fluorescent in situ hybridization (FISH) assay. Design: Testing for HER2 expression by IHC and FISH was performed on 2853 specimens at UT Southwestern Medical Center between the years 2002 to 2011. Quantification of IHC HER2 expression was done by image analysis and scored as positive (>2.0), borderline (1.5 to 2.0) and negative. (2.0, 1.8 to 2.0 and Results: IHC compared to FISH Conclusion: Despite improvements in IHC testing, the FISH assay may be a better method for determining HER2 status. Factors such as tissue fixation, scoring methods and choice of antibodies may contribute to the lower specificity of IHC. In the amplified group, the gene amplification ratio correlated with protein expression, being highest in the IHC positive cases and lowest in those that were negative. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-07-04.

Aims and objectives. This ABC to recovery study evaluated the combined and separate components of preoperative education and the effectiveness of wearing the Papilla Gown. Background. Surgical removal of the breast may lead to activity limitation, self-image issues, discomfort and later complication of lymphoedema. Design. This study used experimental and longitudinal design. Methods. One hundred and forty-five women undergoing mastectomies for stages two and three breast cancer were randomised into four groups: education and Papilla Gown, education only, gown only and control. The outcomes of activity (A), body image (B), comfort (C), knowledge and lymphoedema were assessed at baseline and/or 1 week and 6 months using three measures. All 145 participants completed the study questionnaires at first two measures, and forty-six of these participants completed the questionnaires at 6 months postoperatively. The setting for the study included two clinics and hospitals. To examine statistical significance at each time point after surgery, 2-way anovas were performed on ABC, knowledge and tape measurement to see whether there were any statistically significant differences between the four groups. All reported p-values are two sided. All statistical analyses were performed using sas 9.2 for Windows. Results. The mean age of the sample was 55 years. The study revealed that women who received the combined intervention demonstrated greater activity. Women who wore the gown only had a greater comfort level and decreased lymphoedema. Women that received preoperative education experienced increased knowledge. Conclusions. Outcomes suggest that the combined intervention (ABCs to recovery) can improve recovery following mastectomy. Relevance to clinical practice. The results will be used to further modify the intervention and to increase awareness of nurse practitioners and other healthcare professionals of the specific needs of postmastectomy patients.

Summary To correlate the variable clinical features of estrogen receptor positive (ER+) breast cancer with somatic alterations, we studied pre-treatment tumour biopsies accrued from patients in a study of neoadjuvant aromatase inhibitor (AI) therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to hematopoietic disorders. Mutant MAP3K1 was associated with Luminal A status, low grade histology and low proliferation rates whereas mutant TP53 associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon AI treatment. Pathway analysis demonstrated mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in ER+ breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumor biology but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.

Patient satisfaction in breast surgery is dependent on achieving a balance among all aesthetic subunits. The purpose of this study is to identify which subunit of the breast women consider important and correlate this clinically to improve patient satisfaction following breast surgery. A total of 313 subjects (ages, 20-80) were surveyed using a 25-point survey instrument collected via a telemedicine form. The data was analyzed to determine clinical significance. Of the subjects, 63% selected the upper inner quadrant as the most important subunit. Furthermore, 66% of the subjects indicated defects located in this region would lead them to seek operative intervention and this was consistent for all subgroups. Based on these results, defects in the upper inner quadrant of the breast are more likely to cause patient dissatisfaction. Patient outcomes following surgery can be enhanced by restoring volume and minimizing scars in this upper medial subunit of the breast.

Background and Objectives:HydroMARK® is a newly available biopsy marker for image-guided needle biopsies of non-palpable breast lesions. Objective was to determine if the marker could be utilized independently for lesion localization using intra-operative ultrasound alone.Methods:A single institutio

Background: Oncotype Dx (ODx) is a 21-gene RT-PCR based assay that provides prognostic and predictive information in patients with hormone receptor (HR) positive breast cancer. The test predicts the likelihood of disease recurrence in the form of a recurrence score (RS), which is categorized into low, intermediate and high-risk types. We examined the relationship between ODx RS and histologic parameters, DNA ploidy, tumor markers (ER, PR, Her2, Ki67, p53) expression by immunohistochemistry (IHC). Design: We identified 106 patients with HR-positive invasive breast cancer who were tested for ODx from the department files. Pathologic variables such as, tumor size, grade, histologic type, lymphovascular invasion (LVI) were reviewed. Tumor markers ER, PR, Her2, p53 expression, Ki67 index (KI) and ploidy were performed as part of the patient's diagnostic work-up using standard procedures. Scoring was done by automated image analysis. Results of biomarker expression were compared to the ODx RS. All Her2neu 3+ and 2+ results by IHC were confirmed by FISH. Ploidy was performed by the Autocyte system (Tripath) on Feulgen stained sections. Oncotype RS was reported as low (30). Results: Mean tumor size was 1.96 cm. Of the 106 cases, 87 (82%), 14 (13.2%) and 2(1.8%) were ductal, lobular and mixed types respectively. Grade 1, 2 and 3 comprised 35 (33.0%), 62 (58.4%) and 9 (8.5%) respectively. Twenty-one (19.8%) had LVI. Oncotype RS was low in 56 (52.8%), intermediate in 45 (42.4%) and high in 5 (4.7%). Mean tumor size in low RS group was 2.2 cm versus 1.6 cm in the intermediate/high RS group (p 14%) showed significant correlation with RS (p=0.0055). Her2neu IHC was negative in 43/49 (87.7%) and borderline in 6/49 (12.2%) and all were negative by FISH. Her2 FISH showed 100% (44/44) concordance with Her2 results by ODx. There was no association between DNA ploidy and RS (p=0.7143). P53 expression showed no significant correlation with RS (p=0.2602). Patients in the intermediate/high RS group were more likely to be treated with a combination of chemo plus anti-hormonal therapy (P Conclusions: This study shows a complete concordance between ER IHC and Her2 FISH with RT-PCR by ODx. Low PR scores and high KI predict high RS by ODx. There is a significant association between KI and ODx RS. Ki67 index identifies low and high RS groups, which correspond to the luminal A, and B subtypes of breast cancer respectively. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-08-10.

Background: Molecular subtypes of breast cancer have been characterized by gene expression analysis. Luminal subtypes are hormone receptor (HR) positive and Her2/neu negative. Immunohistochemistry (IHC) has been used as a surrogate test for gene expression. Ki67 is a proliferation marker that identifies high-risk subtype of luminal breast cancer. Recently, the proposed Ki67 index (KI) of 14% was suggested as a cut-off to distinguish between luminal A and luminal B tumors (JNCI. 2009;101:736-750). The oncotype dx (ODx) is a 21- gene test that provides prognostic and predictive information in early stage HR-positive breast cancer patients. The test is reported as low (30) risk recurrence scores (RS) Design: We investigated the relationship between ODx RS and luminal subtypes of breast cancers using the KI of 14% as the cut-off for distinguishing luminal A and B tumors. Biomarker analysis (ER, PR, Her2/neu, Ki67 and p53) was performed as part of the diagnostic work-up using standard IHC procedures. Scoring was done by automated image analysis. Her2/neu FISH was performed on all IHC 2+ and 3 + results. Pathologic parameters such as, tumor size, grade, and presence of LVI were evaluated. Ploidy was performed by the Autocyte system (Tripath) on Feulgen stained paraffin sections. Results: We identified 106 patients with HR positive breast cancer who were tested for ODx from February 2006 to May 2010. 85/106 had Ki67 data available for analysis. 46/85 (54%) were luminal A and 39/85 (46%) luminal B tumors. The mean KI in luminal A was 6.93% versus 31.1% in luminal B (P Conclusion: Ki67 is a useful marker that showed significant correlation with RS by ODx. Luminal A tumors are more likely to be low grade, diploid with low RS compared to luminal B tumors. Ki67 in conjunction with other pathologic parameters may serve as a surrogate marker for the ODx RS. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-08-07.