bluuebunny/crossref_metadata_2025 huggingface dataset:
Central review of discordant samples for microarray-based ER, PR, and HER2 and local IHC/FISH assessment worldwide from 827 patients.
Authors: Wesseling Jelle , Tinterri Corrado , Sapino Anna , Zanconati Fabrizio , Lutke Holzik Martijn , Nguyen Bichlien , Deck Kenneth B. , Querzoli Patrizia , Perin Tiziana , Giardina C , Seitz Gerhard , Guinebretiere Jean-Marc , Barone Julie , Watanabe Toru , De Snoo Femke , Stork-Sloots Lisette , Cusumano Pino
Published: February 2017

11

Background: Differences in fixation and IHC and subjective interpretation can substantially affect the accuracy and reproducibility of estrogen receptor (ER), progesterone receptor (PR) and HER2 expression. The commercially available TargetPrint test measures the mRNA expression level of ER, PR and HER2 and is 98% concordant with centrally assessed ER as presented by Viale et al, SABCS 2011. This study compares results from the microarray-based TargetPrint with IHC and FISH (for HER2 IHC2+) generated by local standard procedures. Methods: Fresh tumor samples (core needle biopsies or surgical) were collected for 831 patients diagnosed with breast cancer stage I to IV (Feb 2008 - Jan 2011) from 22 hospitals from Europe, New Zealand, Japan and US. The results of the IHC/FISH assessments performed according to the local standards at the hospitals were compared to the quantitative gene expression readouts with TargetPrint. Discordant cases were centrally reviewed for IHC/FISH assessment. Results: Of the 831 samples, IHC assessment was unknown for 4 ER/ PR samples; HER2 was unknown for 12 samples. Comparison of IHC and gene expression read out by TargetPrint showed a concordance of 95% for ER; 83% for PR and 94% for HER2. In this study, 3% of all IHC ER positive samples were classified negative by microarray, and 11% of IHC PR positive samples were classified negative by microarray. For HER2, 4% of IHC/FISH HER2 positive samples were classified negative by microarray and 2% of IHC/FISH HER2 negative samples were classified positive by microarray. Most notably, all available 5 ER IHC negative/TargetPrint positive samples turned out to be positive with central re-assessment. HER2 IHC2+ samples with discordant classifications for TargetPrint and local assessment are currently being reviewed for FISH/SISH assessment. Conclusions: Microarray based readout of ER, PR and HER2 status using TargetPrint is fairly comparable to local IHC and FISH analysis in 827 analyzed samples in various hospitals worldwide. However, re-assessment of discordant cases–especially IHC ER-/TargetPrint ER+ cases- confirms TargetPrint to be a useful high quality second opinion for local IHC/FISH assessment.
Interim safety results of eribulin (E) combined with ramucirumab (RAM) in patients (pts) with advanced metastatic breast cancer (MBC).
Authors: Yardley Denise Aysel , Osborne Cynthia R. C. , Richards Paul D. , Daniel Brooke R. , Danso Michael A. , Favret Anne , Bromund Jane , Hsu Yanzhi , Ibrahim Ayman B.
Published: February 2017

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Background: VEGF-mediated angiogenesis contributes to breast cancer (BC) pathogenesis. RAM (IMC-1121B), a fully human IgG1 monoclonal antibody (MAb), targets VEGFR-2, blocking the interaction of VEGF ligands and VEGFR‑2. DC101 (murine anti-VEGFR-2 MAb) impairs vascular function and increases tumor hypoxia in xenograft BC models and inhibits tumor growth in cytotoxic-resistant models. E is a novel non-taxane microtubule inhibitor indicated in MBC pts who have received ≥2 prior chemotherapy regimens, including an anthracycline and a taxane. It is hypothesized that addition of RAM to E as 3rd-5th line therapy in MBC will result in an improvement of median PFS in this ongoing, multicenter, US study. A planned safety analysis of an initial cohort is reported. Methods: Pts with locally recurrent or MBC (HER2+ or HER2-) and 2-4 prior chemotherapy regimens are randomized 1:1 to receive RAM+E or E (E 1.4 mg/m2 Days 1, 8; RAM 10 mg/kg Day 1; q21 days). Pts are stratified by TNBC and prior antiangiogenic therapy status and must have ECOG PS 0-1 and normal LVEF. Planned accrual: 134 pts. Results: Evaluable pts (n=13, 8 RAM+E) received ≥1 dose of RAM+E or E and completed 2 cycles of therapy (or discontinued prior to completing the initial 2 cycles). Median age is 55 yrs. Assessment of adverse events (all cause) revealed nausea, fatigue, headache, and neutropenia were more frequent for RAM+E; anemia was more frequent for E. G1 sensory neuropathy was reported for 1 pt in each arm. One RAM+E pt experienced G3 febrile neutropenia and odynophagia, recovered within a week, and subsequently received reduced dosage (E = 1.1 mg/m2; RAM = 8 mg/kg). No deaths are reported. The safety assessment committee recommended to continue the trial unmodified. Conclusions: Based on preliminary data, the combination of RAM+E demonstrates an acceptable toxicity profile. Accrual continues, with planned updated safety and dose intensity data to be presented at the meeting. [Table: see text]
Acute side effects of intraoperative electron radiotherapy of breast cancer.
Authors: Boelke Edwin , Budach Wilfried , Janni Wolfgang , Zwiefel Karin , Njanang Freddy-Joel , Simiantonakis Ioannis , Matuschek Christiane
Published: February 2017

112

Background: Intraoperative boost irradiation as part of breast-conserving therapy is a perfect method to adequately capture the high risk tumor relapse area. The most homogeneous dose distribution is achieved with electrons. Intraoperative radiotherapy (IOERT) as a boost for breast cancer releases a high single dose of radiation to the breast tissue; therefore acute toxicity is of particular attention. To date there is only inadequate information available on breast cancer patients treated with IORT using electrons applied as a boost. We therefore analyzed the acute toxicity after radiotherapy with 10 Gy as a boost with a minimum follow-up of 3 months. Methods: A total of 69 patients treated with IOERT (10Gy with 5, 7 and 9 MeV electrons) with a dedicated robotic linac (NOVAC 7, New Radiant Technology, Aprilia, Italy) to the tumor bed during breast-conserving surgery as a boost followed by whole-breast radiotherapy (WBRT, 50.4 Gy; 1.8 Gy per fraction) were included in this study. All patients underwent a retrospective follow-up (median, 8 months; range 1-17 months) regarding acute side effects within the first three months. Toxicities were documented using the common toxicity criteria (CTC 4.0 of the European Organization for Research and Treatment of Cancer). Results: The IOERT was well tolerated. As a side effect there was one patient with seroma. Two patients developed chronic pain in the irradiated breast. Two patients developed a secondary wound healing. The remaining patients did not develop any grade 3 or 4 side effects. The observed toxicity rates were not influenced by age, tubus size, electron energy or systemic therapy. Conclusions: After IOERT of the breast using electrons we did not find any unexpected acute toxicity rates.
PIK3CA as a predictor of the clinical efficacy for epirubicin plus docetaxel neoadjuvant chemotherapy in breast cancer.
Authors: Li Xi Ru , Zhang Yan Jun , Liu Mei , Zheng Yi Qiong , Yang Hui Yi
Published: February 2017

113

Background: PIK3CAgene mutations are the most common activating mutations in human breast cancer (BC). Its association with the resistance to herceptin in HER2-positive BC was reported, but whether it’s related to the efficacy of neoadjuvant chemotherapy is unknown. Methods: We reviewed records of 108 patients with BC treated with epirubicin plus docetaxel neoadjuvant chemotherapy between June 2005 and April 2011. 92 patients’ clinical and pathologic objective response data were collected. FFPE tumor biopsies obtained at the time of diagnoses (and before treatment) were collected. EGFR, KRAS, BRAF, PIK3CA mutations and HER2, PTEN, EGFR mRNA expression were analyzed by liquidchip technology. Chi-square test and Fisher’s exact test were used in statistical analysis. A p value less than 0.05 was considered statistically significant. Results: No mutation was detected in EGFR, KRAS and BRAF. The mutation rate of PIK3CA was 35.1% (38/108), and mutation rates of E542K, E545K, H1047L and H1047R were 3.7, 10.2, 3.7 and 17.6% respectively. More PIK3CA mutations were detected in HER2 high expression tumors (p=0.018). No correlation was found between PIK3CA mutations and PTEN, EGFR expression. Clinical response (CR+PR, 63/92) was associated with PIK3CA mutations (p=0.002). However, PIK3CA mutations rate between pathologic complete release (pCR, 7/92) and non-pCR group was not significantly different (p=0.422). Conclusions: PIK3CA mutation may predict better clinical response in BC patients treated with epirubicin plus docetaxel neoadjuvant chemotherapy. More studies are needed to validate these results and the correlation between PIK3CA mutations and pCR.
Barriers to mammography among underserved women in a breast health center outreach program.
Authors: Fayanju Oluwadamilola M. , Kraenzle Susan , Drake Bettina F. , Si Xuemei , Oka Masayoshi , Goodman Melody S.
Published: February 2017

13

Background: An outreach registry of Breast Health Center patients was developed in 2006 to evaluate the effectiveness of mobile mammography among the medically underserved. Registry included collection of medical record data, demographic data, and answers to a questionnaire about perceptions of breast cancer screening. Here, we examine barriers to mammography. Methods: Between April 2006 and May 2011, 9,082 women were registered. Data from registrants’ first screening visit (n= 8,916) were analyzed using multivariable logistic regression examining three outcomes identified as barriers to mammography: cost, fear of pain during the procedure, and fear of receiving bad news. Two-tailed p<0.05 was considered significant. Results: The majority of registrants were black (54%), uninsured (74%), screened on a van (83%), resided in the greater St. Louis region (84%), had an annual income <$20,000 (87%), and reported a good or excellent experience as part of the outreach program (92%). Fears of cost, mammogram-related pain, and bad news were reported by 40%, 13%, and 13% of registrants, respectively. Regression analyses revealed that being employed (odds ratio [OR] 1.109, p=0.0323) and living in the Bootheel of Missouri (OR 2.319, p<0.0001) were associated with a higher likelihood of perceiving cost as a barrier to mammography, while those who had insurance (OR 0.439) and were Hispanic (compared to non-Hispanic [NH] whites [OR 0.338]) were less likely to report cost as a barrier (both p<0.0001). Registrants who were screened on the van (OR 1.633), had insurance (OR 1.391), and were NH black (OR 1.324) were more likely to report fear of procedural pain as a barrier (all p<0.0001). Having insurance (OR 1.378), being NH black (OR 2.458), and being Hispanic (OR 2.980) were associated with reporting fear of receiving bad news as a barrier (all p>0.0001), while older women (OR 0.985, p=0.0001) and women who were screened on the van (OR 0.772, p=0.0026) were less likely to report this concern. Conclusions: Despite provision of free services, cost, fear of procedural pain, and fear of abnormal results remain barriers to mammography utilization among medically underserved women, suggesting the need for more breast health education in this population.
Neoadjuvant therapy (NAT) for breast cancer at the Odette Cancer Centre: What have we been doing and how do we compare?
Authors: Arce Claudia , Gandhi Sonal
Published: February 2017

131

Background: NAT is standard of care for locally advanced breast cancer (LABC). Early breast cancer (EBC) may also benefit, particularly certain subtypes, such as HER2-enriched or basal- like. We developed a clinical care pathway to standardize the assessment and treatment of LABC and higher-risk EBC at the Odette Cancer Centre (OCC). Purpose: Evaluate treatment patterns within the LABC/NAT program at the OCC, and to determine if these patterns changed after the introduction of a clinical care pathway. This study also aimed to evaluate treatment efficacy (pCR rates) by NAT regimen and breast cancer phenotype, as compared to the literature. Methods: Retrospective chart review of patients treated with NAT at the OCC from January 2008 to March 2012. Results: 158 patients were reviewed. Median age at diagnosis was 50 years (28-85), and median tumor size was 7 cm (0-21). 74% were stage IIB-IIIB, and 11.2% were considered non-LABC (or EBC). 65.8% of breast cancers were estrogen receptor positive (ER+), and 29.7% were HER-2 positive (HER2+). 96% of NAT chemotherapy regimens were anthracycline and taxane-based, and trastuzumab was given to 29.7% of HER-2 positive cases. pCR was achieved in 20.9% of all cases and this did not vary by type of chemotherapy regimen; pCR rates did vary by breast cancer phenotype, with 6.25%, 57.5% and 25% pCR achieved for ER+, HER2+ and triple negative (TN) cancers, respectively. Median follow-up was 13 months (0-46), and overall DFS was 90%; survival did not vary by NAT regimen or pCR, but did vary by phenotype, whereby DFS was 100% for HER-2 positive, 90% for ER+, and 78% for TN cancers. There was no significant difference found in types of patients, NAT regimen, or pCR rates before and after the pathway was introduced. Conclusions: Practice patterns at the OCC in NAT for breast cancer remained unchanged before and after development of a clinical care pathway, which was meant to standardize the approach to and to possibly increase the use of NAT from beyond LABC to higher-risk EBC. This is likely due to limited pathway dissemination, but other factors contributing to this should be evaluated. pCR rates by cancer phenotype were similar to those found in the literature.
Thymidylate synthase expression as a predictive factor for response and progression-free survival in metastatic breast cancer patients.
Authors: Seki Hirohito , Jinno Hiromitsu , Hayashida Tetsu , Takahashi Maiko , Kaneda Munehisa , Suzuki Keiichi , Hara Hidenori , Osaku Masayoshi , Yamada Yoshinori , Asamuna Humiki , Kitagawa Yuko
Published: February 2017

132

Background: S-1, an oral fluoropyrimidine formulation that combines tegafur, 5-chloro-2,4-dihydroxypryidine, and potassium oxonate in a molar ratio of 1:0.4:1 has been widely used against solid cancers including gastric, colorectal, pancreatic, lung and breast cancer. In a phase II study, the response rate (RR) was 41.7% and the median survival was 872 days among taxane-pretreated patients with metastatic breast cancer (MBC). However, the predictive factor of S-1 in patients with MBC has not been determined yet. The purpose of this study is to investigate the correlation between 5-FU-related enzyme and clinical efficacy of S-1 in patients with MBC. Methods: Forty-eight patients with MBC were treated with S-1 twice daily at a dose of 80 mg/m2 for 4 weeks, followed by a 2-week rest interval. Laser-captured microdissection was performed from the formalin-fixed, paraffin-embedded tumor sections at surgery and the expression of 5-FU-related enzyme including thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) was evaluated by RT-PCR. Results: The median age was 58 years. ER, PgR, HER2 was positive in 57, 28, and 14% of the entire patients, respectively. The median number of pretreated chemotherapy regimens was 2 (range 0-6). The sites of metastatic disease were the viceral in 25 patients, bone in 9 patients and soft tissue in 17 patients. The overall response rate (RR) was 22.9% (11/48) and clinical benefit rate was 41.7% (20/48). The median time to tumor progresssion (TTP) was 14.3 months (range 6.0 – 22.7). ER, PgR and HER2 status was not significantly correlated with RR. TS expression was significantly associated with clinical efficacy of S-1. Moreover, it is notable that triple negative breast cancer (TNBC) revealed lower TS expression than luminal type (TNBC vs luminal type = 80% (8/10) vs 36.4% (4/11), P= 0.054, OR 0.143, 95% CI 0.020-1.032). According to the correlation between metastatic sites and RR, better RR was noted for soft tissue metastases (soft tissue vs visceral = 25% (5/20) vs 84% (5/6), OR 15.0 (95%CI 1.40–161.05). Conclusions: This study demonstrated that TS is a significant predicitve factor of S-1 in patients with MBC.
Long-term outcome from RTOG 9517: A phase I/II study of accelerated partial breast irradiation (APBI) with mulitcatheter brachytherapy (MCT) following lumpectomy for early-stage breast cancer.
Authors: White Julia R. , Winter Kathryn A. , Kuske Robert R. , Bolton John S. , Arthur Douglas W. , Scroggins Troy , Rabinovitch Rachel , Kelly Tracy R. , Toonkel Leonard M. , Vicini Frank A. , McCormick Beryl
Published: February 2017

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Background: Comparison of APBI to whole breast irradiation post lumpectomy for breast conservation is ongoing in phase III trials. However, APBI has gained acceptance in clinical practice despite relatively limited long-term data. RTOG 9517 studied MCT, one of the earliest methods of APBI, and can uniquely provide long-term cancer outcomes. Methods: Eligibility was stage I/II unifocal breast cancer <3cm, invasive non-lobular histology without EIC, negative surgical margins, and 0-3 positive axillary nodes; no extracapsular extension. The target volume was the lumpectomy cavity plus a 2 cm radial and 1 cm ant/post margin. Low Dose Rate (LDR), 45 Gy in 3.5-5 day, or High Dose Rate (HDR) 34 Gy in 10 BID fractions over 5 days was delivered. A rapid dosimetry review was done to assure dose delivery per protocol. Systemic therapy was per physician’s discretion. The primary endpoint was HDR and LDR MCT reproducibility. This analysis focuses on ipsilateral breast failure (IBF), contralateral breast cancer events (CBE), regional (RF) and distant failure (DF) (cumulative incidence) disease-free (DFS), relapse-free (RFS), and overall survival (OS), (Kaplan-Meier). Results: The median follow up is 12.1 years (yr). 100 patients were accrued from 1997-2000; 98 were evaluable; 65 HDR and 33 LDR MCT. Median age was 62; 88% had T1 tumors; 12% T2; 81% p N0, 19% pN1; 77% ER and/or PR +; 19% ER - and PR -; 33 % received adjuvant chemotherapy and 64% antiendocrine therapy. There have been 6 IBF for a 10 yr rate of 6.2%; 2 IBF were outside the APBI field. There were 5 total RF for a 10 yr rate of 5.2%, respectively. There have been 5 CBE for a 10 yr rate of 4.2%. Failure patterns were: 4 isolated IBF, 1 isolated RF, 8 DF only, 1 IBF+RF, 1 IBF+RF+DF, 1 RF+CBE, 1 RF+DF, 3 CBE, and 1 CBE+DF (21 total failures). Eleven patients have developed DF; 8 have died of breast cancer, 22 have died from other causes. The 10 yr DFS, RFS and OS are 69.8%, 71.9%, and 78.0%, respectively. Conclusions: This multi-institutional phase II trial studying MCT-APBI continues to report durable local regional cancer control rates with long term follow-up. Supported by NCI U10 grants CA21661 and CA37422.
Trade-offs associated with axillary lymph node dissection: Implications of the eligibility versus enrollment in ACOSOG Z0011.
Authors: Krishnan Monica Shalini , Recht Abram , Bellon Jennifer Ruth , Punglia Rinaa Sujata
Published: February 2017

151

Background: Results from ACOSOG Z0011 suggest that axillary lymph node dissection (ALND) may not be necessary for patients following positive sentinel lymph node biopsy (SLNB). Concerns have been raised regarding the generalizability of this trial, given the low-risk patient population. It is uncertain whether a subgroup who would have been eligible for ACOSOG Z0011 but were not adequately represented in the study may still benefit from ALND. Methods: We constructed a decision analysis using a Monte Carlo model to simulate axillary recurrence (ALR) risk, lymphedema, and quality of life of women age 45, 55, and 75 y/o with stage II cancers following breast conserving surgery (BCS) with positive SLNB who were then treated with either ALND and whole-breast radiation (BRT) or BRT alone. Women were divided into two risk groups: those with a risk of residual nodal involvement of 30-60% (high risk); and those with a risk less than 30% (low risk, similar to the Z0011 patients). Probabilities and utilities for health states were derived from previous studies. Results: BRT alone resulted in improved quality-adjusted life expectancy (QALE) in the low-risk group, while ALND with BRT resulted in improved QALE in the high-risk group. Overall survival (OS) was similar at 5 years with both treatment strategies in both groups but was superior with ALND at 20 years in the high risk group (Table). Differences in outcomes decreased with increasing age. In the low-risk group, sensitivity analysis showed BRT alone is preferred unless the ALR risk with BRT is greater than 1.6% or the lymphedema risk with ALND is less than 10%. In the high-risk group, ALND with BRT is the preferred strategy unless the ALR risk with BRT is less than 2.3%. Conclusions: Patients who would have been eligible for ACOSOG Z0011 but are at higher risk of having residual nodal disease following BCS and positive SLNB may benefit from ALND plus BRT rather than BRT alone. [Table: see text]
Surgical techniques, biomaterials, and patient variables that impact peri-operative nipple necrosis in nipple-sparing mastectomy.
Authors: Gould Daniel J. , Hunt Kelly , Liu Jun , Kuerer Henry Mark , Crosby Melissa , Kronowitz Steven J.
Published: February 2017

152

Background: Nipple sparing mastectomy is for treatment of early stage breast cancer and risk reduction in patients at high risk for breast cancer. A high rate of nipple loss after NSM (10% to 30%) has slowed incorporation of NSM into clinical practice. No study has evaluated whether clinical and technical factors contribute to nipple loss by decreasing blood supply to the nipple areola complex (NAC). The objective here was to determine the impact of patient variables and surgical factors on survival of the nipple following NSM and to compare rates of complications of NSM to those of SSM. Methods: We evaluated 233 cases of immediate breast reconstruction following mastectomy at MD Anderson Cancer Center between September 2003 and May 2011. 113 NSM procedures were randomly matched to 120 SSMs based on stage, comorbidities, and age. The NSM group was analyzed for variables that correlated with partial or total nipple loss. Results: In the NSM group, the complication rate was 28%, compared to 27% in SSM (p > 0.99). The nipple loss rate in NSM was 20%. In SSM, axillary node dissection increased complications compared to sentinel lymph node biopsy (p = 0.01). Body mass index, breast ptosis, breast cancer pathology, distance of the lesion to the NAC and use of neoadjuvant chemo or radiation therapy had no effect on nipple loss. Vascular comorbidities and smoking lead to increased nipple loss, with borderline p values (p = 0.09 and p = 0.08, respectively). When compared to A- and B-cup breasts, larger breasts had higher nipple loss (6% and 34%, respectively; p=0.003). Surgical incision location did not affect nipple loss, neither did number of prior NSM procedures performed by the breast surgeon (p = 0.86). Axillary lymphadenectomy (p = 0.13), separate axillary incision (p = 0.25), type of breast reconstruction (p = 0.23), and application of bioprosthetic sling (p = 0.27) may have impacted nipple loss if a larger sample size was studied. Conclusions: Patient variables and surgical technique can alter the rate of nipple loss with NSM. This study helps to define patient populations that may be at risk for necrosis and informs surgeon’s as to the best techniques for reconstruction to decrease the occurrence of nipple loss.
Nipple-sparing subcutaneous mastectomy (NSSM) as dual-plane prosthetic reconstruction using the modified Wise pattern mastectomy, fasciocutaneous flap, and titan-polypropylen-mesh-interponation in women with macromastia.
Authors: Paepke Stefan , Klein Evelyn , Ettl Johannes , Niemeyer Markus , Bronger Holger , Paepke Daniela , Kiechle Marion
Published: February 2017

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Background: Ablative surgery of voluminous, ptotic breasts poses the problem of implant cover of the lower and lateral two thirds that are not coverd by the liftet pectoral muscle. Based on reduction mammaplasty techniques we applied a method that utilizes the excess mammary skin in terms of vertical, lateral, and medial de-epithelialized fascio-cutaneous tissue columns that serve together with a mesh (TiLoop bra) as cover for the subpectoral implant. Methods: Between 06/2009 and 01/2012 we performed 16 nipple and skin sparing mastectomies with marked tissue reduction (defined as difference in weight between implant and resected tissue of more than 300 g) in 7 patients. Indications comprise primary and secondary prophylactic as well as 4 nipple sparing mastectomies after neoadjuvant chemotherapy. Results: Mastectomy weights ranged between 325 and 1100 g; implant volumes ranged between 295 and 800 cm3. There occured five partial necrosis of the nipple-areolar complex (NAC) and three partial skin necrosis at the margin of the vertical incision. Two patients had to be operated on a second time for cosmetic reasons. The overall complication rate was low. Conclusions: The method described herein using the de-epithelialized excess mammary skin and the advantages of the titanized polypropylene mesh archieves stable reconstructions and a safe vascularization of the NAC.
Skin dose effects of postmastectomy chest wall radiation therapy using brass mesh as an alternative to a bolus.
Authors: Healy Erin , Anderson Shawnee , Cui Jing , Beckett Laurel , Chen Allen M. , Perks Julian , Stern Robin , Mayadev Jyoti
Published: February 2017

157

Background: The use of brass mesh as an alternative to a bolus is relatively uncommon in post-mastectomy chest wall radiation therapy (PMRT). This study aimed to characterize the skin dose effects of using 2mm fine brass mesh as an alternative to the traditional tissue-equivalent bolus during chest wall PMRT. Methods: Data was collected from patients who received PMRT using brass mesh at UC Davis Medical Center’s Department of Radiation Oncology between January 2008 and June 2011. Several patient characteristics including age, body habitus, and ethnicity were analyzed along with several disease and treatment characteristics to determine whether or not they had an impact on the skin reaction observed during radiation treatment. In addition to assessing skin toxicity visually using standardized National Cancer Institute scores (NCIS), surface doses were measured for 16 of the 48 patients (33%) to quantify radiation exposure to the chest wall. Results: 48 female patients aged 28-83 received PMRT using brass mesh. As expected, the severity of skin toxicity increased with subsequent doses of radiation with all patients beginning treatment with no skin reaction (NCIS = 0) and the majority of patients completing treatment with either faint to moderate erythema (N = 19, 40%, NCIS = 1) or moderate to brisk erythema (N = 23, 48%, NCIS = 2). In vivo dosimetry analysis revealed surface doses between 81% and 110% of the prescribed dose, with an average of 99% of the prescribed radiation dose being delivered and a standard deviation of 10%. Conclusions: For post-mastectomy chest wall radiation therapy, brass mesh is an effective alternative to the tissue-equivalent bolus. The brass mesh achieved moderate erythema in the majority of patients at the end of treatment and the surface dose was validated using in vivo dosimetry.
Incidence of local recurrence in patients after breast-conserving surgery and postoperative radiotherapy with or without a supplementary radiation.
Authors: Scepanovic Danijela D. , Hurakova Andrea , Lukacovicova Martina , Dolinska Zuzana , Masarykova Andrea , Lukacko Pavol , Pobijakova Margita
Published: February 2017

159

Background: We evaluated the incidence of local recurrence (LR) among patients (pts) who received radiotherapy with/without a supplementary dose of radiation (boost) to the tumor bed after breast-conserving surgery (BCS) for early breast cancer (BC). Methods: In our retrospective analysis (from 2000-2004) 449 pts with stage I/II BC received 50Gy of radiation to the whole breast in 2Gy fractions over a five-week period after BCS. There were 328 pts (73%) with microscopically complete excision (>5mm margins) and 121 pts (27%) with a microscopically incomplete excision (≤5mm margins). Patients with a microscopically complete or incomplete excision were randomly assigned to receive either no further local treatment (190) or an additional localized dose (309) of 10-16Gy, usually given in 5-8 fractions (fr) by electrons/15Gy in 3 fr by HDR interstitial brachytherapy. Results: During a median follow-up period of 79 months (min 20, max 120), the cumulative incidence of LR was 3% for all group of pts (449). The LR was observed in 1 of 190 pts in group without boost and 13 of 309 pts in group with boost. There was statistically significant difference between two groups of pts regarding local recurrence rate (LRR) (p= 0.0218).The 5 year actuarial rates of LR were 1% in group of pts with negative surgical margins versus 8% in group of pts with positive margins [95% CI, 6% (1%-26%)] (p<0.001). Multivariate analysis showed that pts with negative surgical margins had strongly statistically significant influence (p<0.001) and pts with negative lymph/angioinvasion had statistically significant influence on low risk of LR (p = 0.007). The 5 year DFS was 90% and OS was 98% in all group of pts (449). There was no statistical significant difference between two groups of pts regarding DFS and OS. Conclusions: In our analysis, the incidence of LR is low. However, there was better result in no boost group of pts regarding LRR. The cause was in more frequent selection among worse group of pts with positive surgical margins for application of boost (73% vs 52%, p<0.0001). The strong criteria for identifying low risk group of pts for LR were: negative surgical margins and absence of lymph/angioinvasion.
Immunohistochemical analysis of pathway HER2 4B5 performance in breast carcinoma expressing HER4.
Authors: Jay Julie I , Brunhoeber Patrick S , Smith Margie H , Williams Ryan R , Sugarman Michael , Free Heather L , Tast David E
Published: February 2017

16

Background: The ability of pharmacodiagnostic antibodies to specifically detect their target antigen is essential to their performance. Non-clinical protein based models for specificity of two human epidermal growth factor 2 (HER2) pharmacodiagnostic antibodies, Oracle CB11 and PATHWAY HER2 4B5 (4B5) (Ventana Medical Systems Inc., Tucson, AZ, USA), have been reported to demonstrate affinity to both HER2 and HER4. To date there has been no evidence showing that affinity of 4B5 for HER4 impacts the IHC clinical HER2 assay. We therefore sought to investigate whether there exists any risk of the 4B5 antibody detecting HER4-positive but HER2-negative cases as falsely positive due to a hypothetical cross reactivity to HER4. Methods: A HER4 IHC assay was developed by screening ten HER4 antibodies for specificity by staining FFPE blocks of recombinant HEK-293 cells expressing HER1, HER2, HER3 and HER4. Specific HER4 antibodies were then evaluated in breast carcinoma to identify a clone that provided distinct membrane staining in tumour cells. This pattern was used as a reference in order to detect any potential interference of HER4 detection in determining the HER2 score. The HER4 antibody E200 (Epitomics) was selected and used to evaluate a cohort of breast carcinoma cases. The HER2 expression in these cases was then assessed using anti-HER2 clone PATHWAY HER2 4B5 and a HER2 reference antibody, clone SP3 (Spring Bioscience). Results: 117 out of 241 (48%) breast tissue cases evaluated were HER4 positive for membrane staining by IHC using E200. The scoring criteria for determining the HER4 score was based on the system used to score HER2, however a positive score indicated any membrane staining and therefore a 1+, 2+ or 3+ score was considered HER4-positive. 4B5 exhibited similar staining patterns as SP3 in co-expressing HER4 and HER2 tissues indicating that 4B5 was detecting only the HER2 antigen. Eighteen cases were HER4-positive by E200 and level 0 by 4B5 including a HER4 level 3+ case. Conclusions: PATHWAY HER2 4B5, a clinically relevant pharmacodiagnostic antibody for detecting HER2 expression in breast carcinoma, does not demonstrate cross reactivity to HER4 in IHC of FFPE clinical tissues.
Will neoadjuvant chemotherapy affect the lymphatic routes to the sentinel lymph node? Investigation using indocyanine green fluorescence method.
Authors: Tsuyuki Shigeru , Kawata Yukiko , Yamaguchi Ayane , Kawaguchi Kosuke , Okamura Miru , Kawaguchi Nobuko , Kono Yukihiro ,   Osaka Red Cross Hospital Research
Published: February 2017

164

Background: Neoadjuvant chemotherapy (NAC) is a standard therapy for breast cancer. However, the changes in the lymphatic route to the sentinel lymph node (SLN) before and after NAC are unclear. Indocyanine green (ICG) fluorescence method of SLN biopsy (ICG-SLNB) is useful because of its high identification rate of the SLN and ability to visualize lymphatic routes. Using ICG-SLNB, we compared the lymphatic routes to the SLN (sentinel lymphatic routes) before and after NAC and investigated whether chemotherapy affects the sentinel lymphatic routes. Methods: From October 2010 to April 2012 20 patients received NAC. In 13 cases of clinical node-negative cancer, we performed SLNB before NAC. We recorded the sentinel lymphatic routes before NAC and confirmed the routes at surgery after NAC by using the same method. In 7 cases of clinical node-positive cancer, we recorded the localization of SLN and lymphatic routes by using the ICG fluorescence method before NAC. After NAC, we performed SLNB with axillary dissection and recorded the sentinel lymphatic routes by photography and drawing. Results: Regardless of the presence or absence of lymph node metastasis, the SLN and sentinel lymphatic routes could be detected before and after NAC in all cases. All sentinel lymphatic routes reached the same location of the SLN before and after NAC. In 3 cases, the number of sentinel lymphatic routes had increased after NAC, but the location of the SLN was the same before and after NAC. Other cases showed no changes in the sentinel lymphatic routes. In clinical node-positive cases of pathological complete response, there was no metastasis to the SLN, but there were 2 metastases in the lymph nodes after back-up dissection. Conclusions: ICG fluorescence method provided visual confirmation that the sentinel lymphatic routes were not affected by NAC. This result suggests that SLNB after NAC can be used to safely and positively identify the SLN in clinical node-negative patients. Further investigation would be required to safely perform SLNB after NAC in clinical node-positive patients.
Circulating CD68 positive (+) leukocytes in blood samples from patients (pts) with breast cancer (BC).
Authors: Lustberg Maryam B. , Miller Brandon L. , Wu Yongqi , Xue Wei , Deighan Clayton , Carothers Sarah , Berger Michael J. , Shapiro Charles L. , Chalmers Jeffrey J.
Published: February 2017

172

Background: Several different CD45 + leukocyte populations are present in primary breast tumors and stroma (Coussens et al, 2011). These include CD4+/CD8+ T cells and myeloid derived cells such tumor associated macrophages/monocytes (TAMs). TAMs are under investigation as prognostic and predictive markers during chemotherapy (CX). The detection of TAMs has been restricted thus far to tumor tissue. We hypothesized that we can detect changes in CD45+ leukocyte populations in blood samples obtained before and during CX from pts with early and advanced BC. Methods: Venous blood samples from BC patients were collected, and were either directly analyzed or further processed using previously described immunomagnetic negative depletion. Multistep, sequential labeling was performed to first label and fix cell surface markers followed by permeablization for cytokeratins, before and after negative depletion, followed by multiparameter flow cytometry analysis for the following basic markers: CD45, cytokeratins, and EpCAM, and for a subset of patients additional markers including: CD13, CD14, CD68, and CD133. Results: Forty blood samples were analyzed and study is ongoing. Different CD45+ subpopulations were observed in peripheral blood including: a) CD45+, CK+, CD68 negative (-), b) CD45+, CK+, CD68+, c) CD45+, CK+, CD68+, CD14+, and CD16+. In addition, there was a trend in increasing CD 68+ leukocytes after 1 cycle of CX in pts with poor response to therapy or progression of disease. No abnormal cell subpopulations were present blood samples from healthy volunteers. Conclusions: This is the first study to report various peripheral blood leukocyte populations in BC that are similar to those observed in primary breast tumor stroma. The precise origin of these CD45 + cells is under investigation, including additional phenotypic characterization for TAMs. Results will be correlated to patient stage, tumor subtype and response to therapy.
Atypical vascular lesion after radiation therapy for breast cancer.
Authors: Refinetti Ana Paula , Shapiro Richard , Cangiarella Joan , Guth Amber Azniv
Published: February 2017

184

Background: Atypical vascular lesions (AVLs) are known to occur in the setting of radiation therapy after breast conserving surgery for treatment of breast cancer. Their relationship with potential secondary angiosarcoma has yet not been fully characterized. AVLs typically present as single or multiple pink papules in the skin of the breast. Histologic examination reveals proliferation of dilated vascular channels in the dermis with IHC reactive for CD31, CD34 and D2-40. Management consists of local excision to rule out angiosarcoma. Methods: The pathology records of the NYU Langone Medical Center were queried for patients who were diagnosed with atypical vascular lesions. Results: A total of 3 patients with previous history of breast cancer treated with breast conserving therapy (BCT) and radiation therapy were included in this case series. Two patients were diagnosed with DCIS and one was diagnosed with Invasive ductal carcinoma. The median time between the cancer diagnosis and the development of AVL was 5 years (3-9 years). Presentation was an erythematous skin nodule in two patients and progressive telangectasia in one. Diagnosis was made initially by punch biopsy and it was followed by excisional biopsy in all three cases. Only one patient had residual atypical vascular lesion in the excisional biopsy especimen. Conclusions: AVL is a pathological entity with growing importance over the years due to its questionable progression to angiosarcoma. The improvement in survival of patients diagnosed with breast cancer as well as the widespread use of lumpectomy with breast irradiation for the treatment of the disease have caused an exponential increase in the number of patients seen in daily practice after BCT. Clinicians must implement high surveillance of these patients and have a low threshold for further work up of skin changes in the radiated breast in order to early diagnose these lesions since it is yet unknown which ones will progress to angiosarcoma. There are ongoing studies in the development of immunophenotypical markers such as MYC that will be a useful diagnostic tool to differentiate AVL from its malignant counterpart.
Predictors of microinvasion and its prognostic role in ductal carcinoma in situ.
Authors: Sue Gloria , Lannin Donald R. , Killelea Brigid K. , Horowitz Nina Ruth , Chagpar Anees B.
Published: February 2017

188

Background: Predictors of microinvasion in ductal carcinoma in situ (DCIS) are not well understood. We sought to determine factors predicting microinvasion and the prognostic role this plays in patients with DCIS. Methods: A retrospective cohort study of 205 consecutive patients presenting to the Yale Breast Center with DCIS from 2000 through 2003 was performed. A chart review was conducted and bivariate and multivariate analyses comparing patients with and without possible microinvasion were performed. Statistical analyses were done using SPSS software version 19. Results: Of the 205 patients who presented with DCIS and were treated with surgical excision, 51 (24.9%) had evidence of possible microinvasion on final pathology. The median age of all patients was 53.0 years (range 35.8 to 88.9). On bivariate analysis, patients with microinvasion had larger areas of DCIS, and were more likely to have high grade DCIS, of solid type, associated with necrosis and microcalcifications (see table). There was a trend towards white women having a higher rate of microinvasion than black women (26.9% vs. 8.7%, p=0.061). On multivariate analysis, none of these factors were independent predictors of microinvasion. With a median follow-up of 8.5 years, there was no difference in the likelihood of recurrence in the microinvasion vs. no microinvasion groups (6.0% vs. 7.2%, p=1.000). 5-year actuarial overall survival was also not different between the two groups (96% vs. 94%, p=0.202, respectively). Conclusions: Patients with larger DCIS size, higher grade, solid histology, necrosis, and microcalcifications have a higher likelihood of microinvasion. However, the presence of possible microinvasion does not significantly increase risk of recurrence or decrease survival. [Table: see text]
Higher tamoxifen use as chemoprophylaxis in patients with ductal carcinoma in situ (DCIS) in the last decade.
Authors: Roesch Erin E. , Wei Lai , Ramaswamy Bhuvaneswari
Published: February 2017

191

Background: The incidence of DCIS over the last two decades has increased, with over 62,000 new cases diagnosed annually in the United States. Tailored management of DCIS is still a work in progress and currently treatment options are varied. We sought to identify changes in patterns of care in individual and physician choices for surgery and chemoprophylaxis over the last two decades at our institution. Methods: We performed a retrospective chart review and identified 773 eligible patients using the James Cancer Registry and the NCCN database at The Ohio State University between 1990 and 2010. We compared the proportion of patients undergoing mastectomy vs breast conserving surgery (BCT), use of radiation and hormone therapy, and recurrence rates between the years 1990-2000 and 2001-2010 using Chi-square test. Results: There was no significant difference in race (p=0.21) or age (p=0.09) among patients diagnosed with DCIS between 1990-2000 (Group A, N=462) and 2001-2010 (Group B, N=311). There was no significant difference in mastectomy rates between the two groups (31% vs. 27%, p= 0.26). Patients less than 50 years old were more likely to undergo mastectomy in both groups (p=0.02). Use of radiation therapy following BCT was similar between the two groups (52% vs. 53%, p=0.76). Interestingly more patients received hormone therapy during 2001-2010 than 1990-2000 (48% vs. 26%, p < 0.0001). Patients undergoing mastectomy were less likely to receive radiation (2% vs. 74%, p<0.0001) and hormone therapy (25% vs. 39%, p<0.0001). There was no significant correlation between race and type of surgery. We are in the process of comparing recurrence rates between the two groups which will be reported. Conclusions: Previously published studies have reported higher rates of mastectomy among patients with early stage breast cancer in the recent years. Data from our institution over the last two decades did not corroborate this finding, although interestingly we have found increasing use of tamoxifen therapy for DCIS in the second decade. Understanding current practices is helpful in designing future studies for management of DCIS using novel prognostic assays such as Oncotype Dx assay.
Novel surgical technique to selectively remove metastatic axillary lymph nodes in breast cancer patients after neoadjuvant chemotherapy: The MARI procedure—Marking of the axilla with radioactive iodine seeds.
Authors: Vrancken Peeters Marie-Jeanne TFD , Straver Marieke Evelien , Donker Mila , Loo Claudette , Sonke Gabe S. , Wesseling Jelle , Rutgers Emiel J.
Published: February 2017

196

Background: An important benefit of neoadjuvant chemotherapy (NAC) is the increase in breast-conserving surgery. At present the response of axillary lymph node metastases to chemotherapy cannot be accurately assessed. Therefore axilla-conserving therapy is not yet a benefit. We aimed to assess a new surgical method to evaluate the axillary response: the MARI procedure, which stands for Marking of the Axillary lymph node with Radioactive Iodine seeds. Methods: Prior to NAC, proven tumor-positive axillary lymph nodes were marked with a Iodine-125 seed. After NAC, the marked lymph node was selectively removed with the use of a gamma-detection probe. A complementary axillary lymph node dissection was performed to assess whether pathological response in the marked node was indicative for the pathological response in the additional lymph nodes. Results: Tumor-positive axillary lymph nodes were successfully marked with Iodine-125 seeds in 68 patients. The marked lymph node (MARI-node) was surgically detected and selectively removed after NAC in all patients. The pathological response to chemotherapy in the MARI-node was indicative for the overall response in the additionally removed lymph nodes. In 47 patients the MARI-node contained residual disease (n=45 macrometastasis, n= 2 ITC). Thirty-five of them had macro- or micro metastases in the complementary axillary lymph node dissection specimen. In 21 patients the MARI-node was tumor negative. In 2 patients a macro metastasis was found in the additionally removed nodes, in 2 patients ITC were found and in the remaining 17 patients no residual tumor was found in the additionaly removed lymphnodes. (false negative rate of the MARI procedure: 9.5%). Conclusions: This study shows that marking and selectively removing metastatic lymph nodes after NAC is feasible. The tumor-response in the marked lymph node may be used to tailor further axillary treatment, and herewith enabling axilla-conserving surgery after neoadjuvant chemotherapy.
Correlation of receptor activator of nuclear factor kappa b (RANK) expression in breast cancer (BC) at the time of diagnosis with recurrence-free survival (RFS) and risk of bone-dominant metastases (BDM) in the I-SPY 1 trial (CALGB 150007/150012; ACRIN 6657).
Authors: Li Jiali , Yau Christina , Campbell Michael , Esserman Laura , Park John W. , Rugo Hope S. ,   CALGB 150007/150012; ACRIN 6657
Published: February 2017

2

Background: RANK is a tumor necrosis factor receptor family protein that is critical to bone turnover. The ligand to RANK (RANKL) can induce metastases from RANK-expressing tumor cells, and treatment with a RANKL inhibitor can reduce BC metastases (mets) in pre-clinical models and there is an FDA approved drug that targets RANKL. Osteoprotegerin (OPG) is a RANKL decoy receptor that blocks the interaction of RANK/RANKL. I-SPY 1 was a multicenter neoadjuvant trial with well annotated gene expression data and detailed clinical outcomes; we studied the impact of RANK expression on both RFS and BDM. Methods: OPG/RANK/RANKL pathway expression in core biopsies was evaluated at diagnosis in patients (pts) on I-SPY 1, then correlated with ER, intrinsic subtype, stage, response to chemotherapy, site of mets and RFS using the student t-test. Results: Gene arrays were performed on pretreatment tumor from 221 pts; 149 pts have available data with n being ER+. At a median follow-up of 3.5 yrs, 36 pts developed recurrence; 13 pts had BDM, 15 had non-bone mets (NBDM), and 8 pts were not evaluable. RANK, but not OPG or RANKL, was more highly expressed in ER- vs ER+ tumors (p=0.04) and in basal vs luminal A/B subtypes (p= 0.04), but no difference in expression based on tumor grade, node status or response to chemotherapy. Higher (>50%) RANK and lower (<50%) OPG expression correlated with worse RFS (p=0.03). Pts who developed BDM had higher expression of RANK, but not RANKL or OPG compared those with NBDM (p=0.05). After adjusting for ER and intrinsic subtypes, RANK expression was even more significantly correlated with risk for BDM (p=0.004). Conclusions: Higher RANK and lower OPG expression in primary tumor tissue correlates with poor RFS, and high RANK expression is associated with increased risk for BDM. These data suggests that targeting the OPG/RANK/RANKL pathway could be a promising strategy in preventing BDM in pts with high risk BC.