bluuebunny/crossref_metadata_2025 huggingface dataset:
Pregnancy-associated breast cancer (PABC): Czech Young Breast Cancer Study Group Project 35.
Authors: Zimovjanova M. , Tesarova P. , Konopasek B. , Barkmanova J. , Brabec P. , Novotny J. , Pavlista D. , Petruzelka L. B.
Published: February 2017

265

Background: Breast cancer (BC) is the most common cancer in women. 12% of BC occur in women age 20–34. BC is classified as “pregnancy associated” if it is diagnosed during pregnancy or within one year after the delivery (PABC). We propose two distinct subtypes of PABC: BC diagnosed during pregnancy and BC diagnosed post-partum. This distinction is important because epidemiologic data highlights worsened outcomes specific to post-partum cases. The safety of pregnancy after treatment of BC is an important issue for many young women. Current research does not indicate that pregnancy negatively affects survival.

Methods: There are about 95 young women being diagnosed each year with BC in the Czech Republic. A project of clinical registry named “Project 35” was launched in 2005 with the aim to collect data on epidemiology of the disease in young women. The standardization of the multidisciplinary medical treatment, genetic counselling and psychosocial support should result in better clinical outcomes and improve the quality of life.

Results: In our project (n=225) were referred 25 women with PABC, 9 patients with the diagnosis of breast cancer during the pregnancy, 16 patients within one year after the delivery. 2 patients underwent termination of the pregnancy (first trimester) before oncological treatment, in 2 patients anthracycline-based chemotherapy was administered (second trimester), and in 5 patients were induced preterm delivery (third trimester). After delivery we followed standard therapeutic guidelines. All patients are alive but three of them have metastatic disease. From 16 women treated for post-partum BC, 11 patients have complete remission, 2 are alive with metastatic disease, 1 is recovering after the surgery for local recurrence and 2 patients died due to progressive disease. 8 women are BRCA1/2 carriers. 8 women after the successful treatment of breast cancer have delivered of healthy children and are in a complete remission, despite 1 of them with local reccurence of breast cancer.

Conclusions: PABC is rare situation, which needs to be managed individually. These patients should be treated under the supervision of the Oncological Centres. Project 35 is useful framework for the counselling in PABC.
Final results of NKTR-102, a topoisomerase I inhibitor-polymer conjugate, in patients (Pts) with pretreated metastatic breast cancer (MBC) demonstrating significant antitumor activity.
Authors: Garcia A. , Awada A. , Chan S. , Jerusalem G. H. M. , Coleman R. E. , Huizing M. T. , Mehdi A. , O'Reilly S. M. , Hamm J. T. , Barrett-Lee P. J. , Cocquyt V. , Sideras K. , Young D. E. , Brown M. , Zhao C. , Hannah A. L. , Leung A. C. F. , Masuoka L. K. , Perez E. A.
Published: February 2017

269

Background: NKTR-102 is a topoisomerase I inhibitor-polymer conjugate with reduced peak concentration and a continuous concentration profile.

Methods: This was an open-label phase II study in MBC pts following PD on a taxane (T). Pts were randomized to NKTR-102 given IV at 145 mg/m2 over 90-min every 14 or 21 days. Efficacy endpoints included ORR by RECIST v1.0; PFS and OS.

Results: 70 pts (35 per schedule) randomized from Feb 2009 to May 2010 (median follow-up: 10 mo). Median age: 55 (range 33–83). ECOG PS 0/1: 40%/60%. Neoadjuvant and/or adjuvant: 74%. Median number of prior cytotoxic regimens for metastatic disease: 2. All pts had received prior T: 7% (adjuvant); 93% (metastatic). 89% had received prior anthracyclines (A): 63% (adjuvant); 26% (metastatic). 63% had received prior AT only (23% in MBC); an additional 26% had received prior AT/capecitabine (ATC). 61% were ER/PR+; 30% had TNBC; 86% had visceral metastases. Median PFS for q14d, q21d and overall were 3.5 mo, 5.3 mo and 4.6 mo. Median OS for q14d, q21d and overall were 8.8 mo, 13.1 mo and 10.3 mo. Toxicity was manageable, with diarrhea as the most common grade 3+ toxicity, with median time to onset ∼3 mo. Discontinuation from study drug due to AEs: 20%/14% for q14d/q21d. Neuropathy was absent; alopecia was minimal (20%/11% grade 1–2 for q14d/q21d).

Conclusions: NKTR-102 demonstrates significant anti-tumor activity in pts with advanced MBC, including poor prognosis pts with TNBC and having received prior ATC. A phase III study is being planned in patients with MBC previously treated with taxanes.

[Table: see text]
Survival of patients with locally advanced triple-negative breast cancer after neoadjuvant platinum-containing chemotherapy: Experience of a single institute.
Authors: Ibrahim E. A.
Published: February 2017

274

Background: Primary systemic chemotherapy is a standard approach to treating women with locally advanced breast cancers, with higher survival rates reported among patients who attain a pathologic complete response. Triple-negative breast cancer is a special biological entity that remains major challenge to oncologist. Around 12%-20% of breast cancers are triple negative. The current phase II study was conducted to evaluate the pathological complete response (pCR) using cis-platinum containing regimen as neoadjuvant chemotherapy in locally advanced triple negative breast cancer.

Methods: Eighteen women with stage III triple negative breast cancer who were recruited between July 2007 and February 2010 at King Fahad Specialist Hospital, Dammam, Saudi Arabia. Neoadjuvant chemotherapy consisted of 4 cycles of AC or FEC 100, followed by 4 cycles consisted of docetaxel-cisplatin every 3 weeks. Primary end point was pathological complete response.

Results: Median age: 49 y (24-70); premenopausal: 16; 25% were below 35 years of age; Median tumor size: 9 cm (3.5-19); Grade III: 15; Stage IIIA: 3, IIIB:14, IIIC:1; all but 2 had positive nodes at diagnosis (89%). Clinical evaluation of response by RECIST criteria pre surgery: OR: 17/18 (94%), CR: 9 (50%); PR: 8 (44%).The second sequence with D-Cis-T doubled the rate of clinical CR obtained with AC/FEC. One patient was not operated due to disease progression. Pathological assessment, revealed that 8 (47%) pts had no residual invasive carcinoma in the breast; 3 (18%) had residual occasional scattered tumor cells less than 5 mm (pT1a); 10 (59%) had negative nodes; 8 achieved CpR and 2 nCpR. Patients with residual invasive component and/or nodal involvement had high baseline Ki 67 level. After a median follow up of 24 months, cumulative overall survival at 24 months is 88.9% for whole group. Cumulative overall survival in relation to response was 100% for patients who achieved pCR while overall cumulative survival rate for patients without pCR was 83.3% without statistical significance.

Conclusions: This cisplatin based neoadjuvant chemotherapy regimen was well tolerated and achieved a high rate of pCR/npCR.
Albumin-bound paclitaxel (ab-pac) versus docetaxel for first-line treatment of metastatic breast cancer (MBC): Final overall survival (OS) analysis of a randomized phase II trial.
Authors: Gradishar W. J. , Krasnojon D. , Cheporov S. V. , Makhson A. , Manikhas G. M. , Clawson A. , Bhar P.
Published: February 2017

275

Background: We previously reported the results of a phase II study evaluating the efficacy and safety of three different dosing regimens of ab-pac and docetaxel for the first-line treatment of MBC (Gradishar et al. J Clin Oncol. 2009;27:3611-3619). Here we report final OS outcomes.

Methods: Patients (N = 300) with previously untreated MBC were randomized to 1 of 4 treatment arms (arms A–D listed in table). A step-down statistical approach was used for pairwise comparisons of treatment groups.

Results: Patients (N = 300) with previously untreated MBC were randomized to 1 of 4 treatment arms (arms A–D listed in table). A step-down statistical approach was used for pairwise comparisons of treatment groups. These OS data were consistent with the investigator assessment of overall response rates (ORR) and progression-free survival (PFS) that were previously published. Rates of grade (gr) 3 sensory neuropathy (SN) were 21%, 9%, 22% and 12%, respectively in arms A, B,C, and D (p= 0.082). There were no cases of gr 4 SN. The median times to improvement to ≤ gr 2 SN were 22, 22, and 20 days for arms A, B, and C and 37 days for arm D. Gr 3/4 neutropenia occurred less frequently with ab-pac vs docetaxel (gr 3: 39, 20, 35, and 19% in arms A,B,C, and D, respectively; gr 4: 5, 5, 9, and 75%, p < .001 for gr 4).

Conclusions: Ab-pac qw 3/4 at 150 mg/m2 resulted in a 33.8 mo OS, a longer OS than historically achieved with taxane monotherapy in MBC. The 150 mg/m2 qw 3/4 dosing regimen provided the best clinical outcome in this phase II trial in patients with MBC.

[Table: see text]
Evaluation of recurrence score and traditional clinicopathologic metrics in a large ER-positive, lymph node–negative patient cohort.
Authors: Baehner F. L. , Liebermann N. , Shak S. , Klang S. , Yoshizawa C. , Lior s. , Siegelmann-Danieli N.
Published: February 2017

30

Background: The 21 gene Recurrence Score (RS) assay provides prognostic and predictive info for ER+ breast cancer. In a large cohort of ER+, HER2 normal, lymph node negative (LN-) patients, the distribution of RS and RS groups, within categories of patient age, tumor size, grade, and joint categories (e.g., tumor size versus patient age), were examined.

Methods: 2,097 pts from Clalit Health Services (CHS) and 484 from Maccabi Health Services (MHS) in Israel, had the RS ordered between 1/08-6/10. 1864 were LN-, ER+ and HER2 nrml (LN- grade 3 tumors of MHS pts were required to be <2 cm). Pt age, tumor size and grade were obtained for 100%, 99% and 82%. Distributions of RS were compared among categories of the traditional factors and Spearman correlation coefficients (and 95% CI) were calculated to assess the association between the RS and them.

Results: 99.3% were female. Standard distributions by age were: 23-40 yo, 3.2%; 40-49 , 16.5%; 50-59, 30.4%; 60-69, 32.8%; 70-85, 17.1%. By tumor size: <1 cm, 12.5%; 1-2cm, 65.8%; >2-3cm, 17.3%; >3cm, 4.5%. By grade: 1, 18.1%; 2, 63%; 3, 18.9%. 79.7% were ductal & 12.5% lobular. 81.9% were IHC PR+. Spearman correlation coefficients (and 95% CI) for continuous RS with standard metrics: age, -0.09 (-0.13, -0.04); tumor size (cm), 0.07 (0.02,0.12); grade, 0.33 (0.28, 0.37). Pts <50 yo, 14.2% had high RS disease (dz); ≥50 yo 10.3% had high RS dz. In tumors ≤2 cm, 16% had high RS dz; > 2 cm 30.7% had high RS dz. Of grade 1 tumors 1.4% had high RS dz and 30.7% had intermediate RS while 22.8% of grade 3 tumors had low RS dz. 7.5% of PR+ tumors had high RS dz and 20.1% of PR- tumors had low RS dz. Joint categories will be presented.

Conclusions: There is a range of RS biology across patient age, tumor size and grade. The RS cannot be predicted by clinicopathologic variables.

[Table: see text]
Factors impacting survival after diagnosis of breast cancer (BC) brain metastases (BM).
Authors: Aicardi J. , Moore D. H. , Rugo H. S. , Chien A. J. , Park J. W. , Moasser M. M. , Munster P. N. , Melisko M. E.
Published: February 2017

31

Background: With improvements in control of systemic disease, subsets of breast cancer patients (pts) including those with HER2+ and triple negative (TN) BC appear to have an increased risk of BM. We sought to evaluate factors influencing outcomes after diagnosis of BM.

Methods: We collected treatment information and outcomes for pts diagnosed with BM who received ongoing care at our center from 1997 to 2011. We correlated clinical, treatment, and pathologic characteristics including age, hormone receptor (HR) and HER2 status, Karnofsky Performance Score (KPS) and number of BM (#BM) at diagnosis with outcomes. Patients were characterized as one of three subtypes: HR+/HER2+, HER2+, or TN.

Results: 184 patients are included in this analysis. Median time to BM diagnosis (TTBM) was 38.8 months (mo) (range, 0–274); median survival (OS) after diagnosis of BM was 14.9 mo. Both varied by tumor subtype. Multivariate analysis revealed that TN disease, age >50 and KPS <90 were associated with decreased OS after diagnosis of BM. Progression of systemic disease and >3 BM at diagnosis were univariate predictors of decreased OS (P=0.0005 and P=0.02 respectively) but were not significant in multivariate analysis. Pts treated with gamma knife (GK) as initial therapy followed by whole brain radiation therapy (WBRT) as salvage had similar OS to patients who received WBRT first then had GK as salvage (31.8 vs. 28 mo). Patients who received WBRT or GK only had worse OS (7.7 and 16.3 mo respectively). Since the year 2000, OS after diagnosis of BM remained relatively constant.

Conclusions: Underlying tumor biology appears to drive outcomes, and patients with TN BC continue to have a poor prognosis after BM diagnosis. Despite the reported improvement in OS following BM diagnosis compared to previous decades, we did not observe a reduction in risk of death based on calendar year of diagnosis of BM.

[Table: see text]
Male breast carcinoma in United States: Survival rate and determinants of prognosis.
Authors: Talluri S. , Kakarala R. , Karedan T. , Kakarala M.
Published: February 2017

32

Background: Male breast cancer (MBC) is rare and accounts for less than 1% of all cancers in men. It causes significant morbidity and mortality due to late diagnosis. The primary objective of our study is to update information about the receptor status, pathology, survival rates, and prognostic factors for MBC. Our secondary objective is to determine racial differences in survival of MBC and compare tumor characteristics with female breast cancer (FBC) patients.

Methods: We analyzed a retrospective cohort of breast cancer patients included in National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) from 1990 to 2007. Differences between patient and disease characteristics at the time of diagnosis among MBC and FBC patients were compared using chi-square test. Overall survival was estimated using Kaplan-Meier method. Cox proportional hazards regression model was used to determine the independent variables that affect survival.

Results: We included 2,475 men and 393,259 women with breast cancer in our analysis. Median age at diagnosis was higher in men compared to women (67 vs 61years). Men had more frequent lymph node involvement (32% vs. 22%), ER positivity (66% vs. 57%) and PR positivity (57% vs. 49%) breast cancer than women (P<0.001). Overall median survival in MBC was 9 years, 5-year survival was 63% and 10-year survival was 43%. Increased age, larger tumor size, higher grade, lymph node involvement, ER and PR negative status were significantly associated with decreased survival in univariate analysis (P <0.05). In multivariate analysis, age > 65 years at the time of diagnosis, larger tumor size, positive lymph node status, ER negative status and poorly differentiated grade were associated with decreased survival (P <0.02). However PR status was not a significant predictor of survival. The median survival in African American males was lower as compared to Caucasians (7.08 vs. 9.2 yrs.) (P=0.02).

Conclusions: Male breast cancer differs from female breast cancer in important biological characteristics with a higher age at diagnosis and frequent lymph node involvement. Age greater than 65 years, tumor size, grade, lymph node involvement and ER status of the tumor are independent predictors of survival in MBC.
Immunologic markers associated with favorable prognosis in breast cancer patients: Role of innate immune system.
Authors: Ascierto M. L. , Kmieciak M. , Idowu M. O. , Bedognetti D. , De Maria A. , Bear H. D. , Wang E. , Marincola F. , Manjili M.
Published: February 2017

43

Background: Recognition of tumor cells by NK cells is mediated by the interaction of activating and inhibitory NK cell receptors with ligands expressed on the interacting cell. In addition to inhibitory and activating receptors, NK cells express adhesion molecules that allow conjugate formation between NK cells and their tumor targets. We have recently identified by transcriptional analysis of breast tumor specimens a signature of 5 genes, which included B cell response and interferon signaling, found to predict with > 85% accuracy relapse-free survival. In the current study we analyzed by gene expression profile, whether a differential expression of activatory and inhibitory receptors and gene involved in NK cell-target interactions could be identified in relapse and relapse free patients.Methods: RNA extraction and gene expression analysis was performed on tumor specimens with at least 10% of infiltrating cells deriving from 9 from breast cancer patients who had either 3-7 years relapse-free survival (n=9) or developed tumor relapse within 1-3 years after the initial treatment (n=8). Data were analyzed by BRB tools and Partek software.Results: Our results showed that patients with a favorable prognosis showed increased expression of genes involved in NK interaction with tumor cells and NK activating signaling. In particular an up-regulation of leukocyte function-associated antigen 1 (LFA-1) gene, typically involved in NK cells adhesion to target cells and DNAM 1, usually associated with activation of NK cells and considered one of the major protagonist of NK- Dendritic cells crosstalk, was observed to occur in relapse free patients. In addition, an up regulation of CD96 and CRTAM which, like DNAM 1, promote NK cell-target cell adhesion by interacting with the Necl2 and poliovirus receptor (PVR), was observed in relapse free patients.

Conclusions: Our observation suggests that the NK signatures are associated with favorable outcome in breast cancer and allow us to generate new hypothesis on the role of innate immunity in this contest.
Evaluation of ER/PR and HER2 status by RNA sequencing in tissue core biopsies from preoperative clinical trial specimens.
Authors: Kamalakaran S. , Lezon-Geyda K. , Varadan V. , Banerjee N. , Lannin D. R. , Rizack T. , Sikov W. M. , Abu-Khalaf M. M. , Janevski A. , Harris L. ,   Brown University Oncology Group
Published: February 2017

46

Background: Next-generation sequencing for measuring RNA (RNASeq) offer increased sensitivity, dynamic range and provide unbiased detection of all transcripts. To evaluate the clinical utility of such methods, we sequenced entire transcriptomes from fresh-frozen biopsies in a cohort of 120 patients enrolled on a preoperative therapy trial receiving carboplatin, nab paclitaxel and either bevacizumab (HER2-) or trastuzumab (HER2+).

Methods: Total RNA was extracted and amplified from frozen breast core biopsies and libraries constructed using TruSeq (Illumina). Sequencing was performed on the Illumina GAII platform. 75bp reads were mapped using Tophat and transcript abundance in FPKM units (Fragments per kilo-base of mRNA per million reads) calculated using Cufflinks. CLIA approved assays were performed for ER, PR, HER2 (IHC+/- FISH) on patient tumors. Four tumors from each subtype (ER +ve/HER2 -ve; HER2 +ve; ER/HER2 -ve) were analyzed for correlation with clinical status. PAM50 classification will be provided for verification of molecular subtypes.

Results: RNA-Seq library construction/sequencing were successful in 12/12 samples with 50-90% reads mapped. ER +ve tumors ranged in FPKM values from 1.76-22.67 and ER -ve tumors ranged from 0.00-0.79. i.e. ER RNASeq measurements can separate clinical ER status. HER2 +ve tumors ranged in FPKM values from 2.62-21.71 and HER2 -ve tumors from 0.21-1.79. Of note, 7/8 HER2 -ve tumors ranged from 0.21-0.87 with one ‘outlier’ at 1.79±0.3. This outlier was HER2 IHC 2+, FISH ratio 1.1 with 45% of tumor cells with polysomy chromosome 17. Correspondence of ER/PR and HER2 status with molecular subtyping by PAM50 analysis will be presented.

Conclusions: RNASeq has potential to provide in depth analysis of the breast cancer transcriptome and a single analysis test for standard markers. In addition, RNASeq may uncover unexpected expression patterns in conventionally-defined HER2 -ve tumors. If reproducible in larger datasets, this technology may provide both standard and novel information previously unavailable to oncologists and their patients.
Intermethod comparison of breast receptor studies by immunohistochemistry and quantitative RT-PCR (21 gene assay).
Authors: Fulton R. S. , Baehner F. L.
Published: February 2017

48

Background: The ASCO/CAP Guidelines mandate that laboratories performing HER2 and hormone receptor analyses monitor and correlate their results with results obtained from outside testing. Herein, we evaluate the concordance between results obtained by the 21 gene assay (ODx) with those performed by immunohistochemistry (IHC) at the Kaiser Permanente Northern California Regional IHC Laboratory (KP-NCAL).

Methods: Sequential specimens from KP-NCAL were evaluated by IHC for ER (SP1), PR (PgR636) using 5% staining for positivity and HER2 (4B5) using >30% with 3+ positivity. Standardized quantitative RT-PCR analysis for ER, PR and HER2 was performed using pre-defined cutoffs of 6.5, 5.5, 11.5 units. Reference normalized expression measurements ranged from 0 to 15, where each 1-unit increase reflects about a 2-fold increase in RNA. The percent positive agreement (PPA) and percent negative agreement (PNA) was calculated for each of the three markers. For the purposes of this inter-method comparison we define ODx as the reference test; in this comparison, a “true positive” is IHC+ and ODx+. A “false positive” would be IHC+ and ODx-.

Results: Evaluable data was obtained from 216 sequential patients from 11/2009 to 5/2010 with both IHC (KP-NCAL) and the 21 gene assay (ODx) results. The HER2 PPA was 100%, PNA 99.4%. The ER PPA was 99.1%, PNA 100%. The PR PPA was 92%, PNA 52%.

Conclusions: There is a high degree of agreement between KP-NCAL IHC and ODx results for ER and HER2. This level of agreement is particularly striking given that in >90% of cases, IHC was performed on an initial biopsy, while the RT-PCR assay was performed on a subsequent excision specimen. The negative agreement for PR was moderate and suggests a possible lack of sensitivity in the IHC assay that needs to be studied further.

[Table: see text]
Risk factors of brain metastasis in a series of Egyptian breast cancer patients: A single-institution experience.
Authors: Azim H. A. , Malek R. A. , Abdelmonem D. , Amin S. , Abdelsalam M.
Published: February 2017

50

Background: Incidence of cerebral metastasis is increasing among breast cancer patients. Many factors have been reported associated with increased risk of brain metastasis. The aim of this retrospective analysis is to investigate the predictive factors for the development of brain metastasis in breast cancer patients.

Methods: We retrospectively analyzed histologically proven breast cancer patients who presented to Cairo Oncology Center (COC) in the period from 1999 till 2008, with follow up period of 6 months at least for those in adjuvant setting. The following factors were analyzed: age, tumor size and grade, nodal status, ER, PgR and HER2 over-expression status.

Results: Our study included 2,338 patients. 96 patients (4.1%) experienced brain metastasis during the course of their disease. 3 patients had brain metastasis among other sites of distant spread at first presentation to COC. 30 out of 96 patients (31.25%) with localized breast cancer had brain metastasis at first relapse with 13 (13.5%) of them had isolated brain metastasis. In a median follow-up of 37.1 months (6-277) the median time to develop brain metastasis was 26.5 months (0-144). Based on univariate analysis, the following variables were associated with shorter time to develop brain metastasis: tumor size more than 5 cm (HR = 2.1, 95% CI 1.14-3.87), lymph node involvement at diagnosis (HR = 1.57, 95%CI 1.17-2.10), ER negativity (HR = 1.58, 95%CI 1.33-1.73), PgR negativity (HR = 1.55, 95%CI 1.29-1.72) and HER2-neu over-expression (HR = 2.68, 95%CI 1.51-4.75). On multivariate analysis, only patients with lymph node involvement at diagnosis and those with HER2-neu positive breast cancer were associated with shorter time to develop brain metastasis.

Conclusions: We concluded that HER2 over-expression as well as lymph node involvement are the 2 main factors associated with shorter time to develop brain metastasis. These patients could be good candidates for trials investigating the role of any prophylactic intervention to decrease their risk to develop brain metastases.
Predicting possibility of positive non-sentinel nodes in sentinel node–positive breast cancer patients: A Singapore series.
Authors: Yong W. S. , Chang M. H. , Chen W. J. J.
Published: February 2017

51

Background: Sentinel lymph node (SLN) biopsy is an accepted method for determining the axillary status in early breast cancer patients. If positive, a standard axillary clearance is performed. However, recent studies have shown that many of these patients may not have additional positive non sentinel nodes, and the removal of these additional nodes may not be necessary or confer any benefit. We set out to identify factors that determine non sentinel node positivity and whether this could be predicted from our series of early breast cancer patients.

Methods: We retrospectively reviewed 337 of our early breast cancer patients from 2005 to 2008 who had atleast one positive sentinel node and had undergone a full axillary clearance. Tumour factors and sentinel node variables were collected and compared between those patients with additional positive non sentinel nodes and those with no positive nodes in the axillary clearance.

Results: Five factors were found on univariate analysis to be associated with non sentinel node positivity. They are ratio of positive SLN to total number of SLN, number of positive SLNs, size of metastasis in the SLN, tumour size and lymphovascular invasion. The first 3 factors were used to model a logistic-regression model which has good prediction ability to predict positivity of non SLNs (value under ROC curve 0.726 [95% CI 0.666-0.786]).

Conclusions: Tumor factors and SLN variables are able to help us predict the possibilty of additional positive non SLN once at least a SLN is positive. This can help the surgeon and patient in the decision making process on the need for a full axillary clearance.
Is modified Bloom-Richardson grade a reliable predictor of breast cancer recurrence?
Authors: Yap K. K. L. , Efiom-Ekaha D. N.
Published: February 2017

52

Background: Modified Bloom-Richardson (MBR) grade is a pathologic grading system for breast cancer that has been shown to have prognostic significance in patients with node-negative disease. Oncotype DX Score is a 21-gene expression analysis that has been clinically validated as a reliable predictor of recurrence risk for node-negative estrogen receptor-positive breast cancer. A score of less than 18 signifies a low risk of recurrence, a score of 18 to 31 signifies an intermediate risk and a score greater than 31 signifies a high risk. Several reports have questioned the concordance between the Oncotype score and MBR grade. The objective of this study is to evaluate the concordance between Oncotype score and MBR grade, thereby ascertaining if MBR is a reliable predictor of breast cancer recurrence.

Methods: An IRB-exempted restrospective chart review of female patients at Wellspan Group who had Oncotype DX analysis in 2008 and 2009 was carried out. Data collected included Oncotype DX score, MBR grade, BMI and menopausal status. Data were analyzed to determine the association between Oncotype DX score and MBR grade.

Results: A total of 125 patients were identified. Of these, 107 had MBR grades available. The remaining patients did not have MBR grade as it was not applicable to their breast cancer type. The mean Oncotype scores were 15.11 (95% CI 13.33-16.89) for patients with MBR grade 1 carcinoma, 20.31 (95% CI 17.90-22.72) for MBR grade 2 carcinoma, and 39.93 (95% CI 30.05-49.80) for MBR grade 3 carcinoma. The mean Oncotype score differences were 5.201 (P = .007, 95% CI 1.46-8.94) between MBR grades 1 and 2, and 19.616 (P < 0.001, 95% CI 14.14-25.09) for MBR grades 2 and 3. The ranges of Oncotype scores for MBR grade 1, grade 2 and grade 3 were 3 to 36, 9 to 56 and 20 to 70 respectively.

Conclusions: MBR grade may predict breast cancer recurrence risk reliably as there is acceptable concordance between MBR grade and Oncotype Dx recurrence risk.
Functional metabolic tomographic optical breast imaging (TOBI) to monitor response to neoadjuvant therapy in breast cancer.
Authors: Carp S. A. , Wanyo C. , Specht M. C. , Schapira L. , Moy B. , Finkelstein D. M. , Boas D. , Isakoff S. J.
Published: February 2017

60

Background: Recent studies using near-infrared optical measurements in breast tumors have demonstrated the promise of early monitoring of neoadjuvant chemotherapy (NAC) to predict outcome. Technologies to date have focused primarily on static measurements. Dynamic optical imaging, in conjunction with fractional mammographic compression, offers access to multiple functional and metabolic tissue biomarkers that may be used to predict treatment response. We have developed a novel tomographic optical breast imaging (TOBI) device to evaluate the early (day 7) prediction performance of this advanced technology.

Methods: We are conducting a pilot feasibility study in female patients with unilateral locally advanced breast cancer undergoing standard-of-care NAC. Pre-treatment and day 7 post-treatment TOBI scans are obtained, with additional scans on day 1 of each subsequent chemotherapy cycle. The affected and contralateral normal breasts are compressed to 6-8 lbs of force and optical images are acquired once every 2 seconds for two minutes. Time-resolved oxy-(HbO), deoxy-(HbR), and total-(HbT) hemoglobin concentration and hemoglobin oxygen saturation (SO2) are calculated. The compression-induced rate of change of HbT correlates with changes in tissue blood volume indicative of biomechanical properties and the evolution of tissue SO2 estimates tissue metabolism.

Results: We report initial data from two patients. One patient had a near-pathologic complete response (responder) and showed 21% and 23% decreases in HbT and HbR, respectively. The second patient had no significant response (non-responder) and had 2% and 1% decreases in HbT and HbR, respectively. Interestingly, the responder showed a dynamic decrease in HbT during compression in the tumor region at day 0 that disappeared at day 7, while the non-responder had similar rates of HbT change at both scans.

Conclusions: We demonstrate for the first time the feasibility of dynamic optical breast tomography and show that optically derived parameters may be sensitive to therapyinduced changes in breast cancer. These dynamic measurements may provide novel insight into the physiologic changes in breast tumors during treatment.
Correlation of efficacy between rash and lapatinib/capecitabine therapy in Japanese HER2-positive metastatic breast cancer patients.
Authors: Nagai S. E. , Inoue K. , Kaneko S. , Uchida S. , Higuchi T. , Hayashi Y. , Yoshida T. , Takei H. , Kurosumi M. , Tabei T.
Published: February 2017

62

Background: Lapatinib (L) is an oral dual-tyrosine kinase inhibitor with specificity for both EGFR and HER2. A phase III randomized trial (EGF100151) demonstrated that L+ capecitabine (C) is superior to C alone in patients with HER2-positive advanced breast cancer that progressed following prior therapy including trastuzumab. Although, Japanese phase I/II trial (EGF109749) demonstrated better response rate and higher rate of rash over a previous phase III trial. Recent reports demonstrated the correlation of efficacy between EGFR targeted therapy and rash in colon cancer. In lung cancer EGFR mutation, which are predominantly found in patients of East Asia origin are highly sensitive to EGFR-TKI. Analyzing correlation of efficacy between rash and EGFR targeted therapy is important in breast cancer.

Methods: From June 2009 to February 2010, we treated 28 HER2-positive MBC patients who developed progression after anthracyclines, taxanes and trastuzumab based regimens with L 1,250 mg p.o. daily plus C 2,000 mg/m2 p.o. days 1-14 q 21 in Saitama Cancer Center. EGFR status was evaluated by immunohistochemistry. We analyzed the correlation among rash, clinical outcome and EGFR status.

Results: Fourteen (50%) patients experienced rash, which were two grade 3, four grade 2 and eight grade 1. Rash experienced group showed superior response rate (77% : 24%, p<0.05) and median survival time (N/A: 259 days, p<0.05) over non-rash group. EGFR status has no correlation between rash and clinical outcome.

Conclusions: According to our single institute experience, rash might be predictive factor in Japanese HER2 positive breast cancer patients treated with L+C therapy.
High spatial and temporal resolution breast DCE-MRI: A feasibility study.
Authors: Roy N. , Oh K. Y. , Kettler M. D. , Tudorica L. A. , Huang W.
Published: February 2017

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Background: The typical 1-2 min low temporal resolution (tRes) of conventional gradient-echo (GRE) breast dynamic contrast-enhanced (DCE) MRI precludes accurate quantitative pharmacokinetic (PK) analysis. The commercially available GRE-based TWIST (time-resolved angiography with stochastic trajectories) sequence employs an alternative k-space sampling scheme to provide high spatial and temporal resolution for dynamic imaging, originally intended for time-resolved MR angiography. Here we sought to evaluate the feasibility of breast DCE-MRI with the TWIST sequence, using both tumor morphology and quantitative PK analyses.

Methods: 22 patients with 25 mammography-detected suspicious lesions underwent TWIST DCE-MRI on a 3T Siemens system prior to biopsy. The axial bilateral images were acquired with 20 s tRes and 1.0x1.0x1.4 mm3 spatial resolution (sRes). Immediately after TWIST DCE-MRI, a single DCE image set was acquired in 68 s using a conventional GRE sequence with the same sRes. Blinded to pathology, 3 radiologists compared lesion morphology assessments from the last TWIST DCE and the conventional images, and gave MRI BIRADS scores based on morphology and qualitative kinetic curve analyses. The TWIST DCE lesion signal time-courses were also subjected to Shutter-Speed Model PK analysis.

Results: Normal parenchyma S/N ratios were not statistically different between TWIST and conventional GRE images. All readers indicated 88% [95% CI: (68%, 97%)] agreement in morphology evaluation between the TWIST and conventional DCE images. The degree of inter-reader agreement was substantial (κ = 0.75), as was the agreement in BIRADS scores (κ = 0.76). Pathology revealed 8 malignant and 17 benign lesions. Based on MRI BIRADS scores, all 3 readers attained 100% sensitivity and 82% specificity. With PK analysis, a Ktrans (contrast agent plasma/interstitium transfer rate constant) cut-off value of 0.1 min-1 further improved specificity to 94%.

Conclusions: TWIST breast DCE-MRI provides both high tRes and sRes for accurate quantitative PK analysis and morphology evaluation, respectively. Utilizing TWIST for clinical breast DCE-MRI with quantitative PK analysis is feasible and may improve MRI interpretation.
Xenotransplantation of surgical specimens of human breast cancer directly into genetically engineered prolactin-humanized immunodeficient mice.
Authors: Yang N. , Utama F. E. , Yanac A. F. , Liu C. , Rosenberg A. L. , Rui H.
Published: February 2017

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Background: Prolactin is an important hormone in mammary gland biology and is indispensible for lobulo-alveolar development during pregnancy and homeostasis during lactation. Prolactin has also been implicated in promoting proliferation, survival, and/ or differentiation of breast cancer. Importantly, murine and bovine prolactin, which are the major lactogens in current laboratory experimental conditions in vivo and in vitro, fail to effectively activate human prolactin receptors because of species incompatibility. Therefore, current established human breast cancer cell lines have been selected in the absence of human prolactin and do not represent the potential subgroup of cancers that depends on prolactin for survival or growth.

Methods: In an effort to improve in vivo preclinical modeling of human breast cancer and to establish new human breast cancer lines that are prolactin-dependent or prolactin-sensitive, we used genetic-engineering to generate a human prolactin knock-in mouse line, which expresses physiological levels of human prolactin in place of mouse prolactin. We have crossed the prolactin-humanized mouse line into the immunodeficient NSG strain for effective xenotransplantation studies. Fresh surgical specimens from breast cancer patients were directly transplanted orthotopically into female mice within 2 hours of surgery. We then followed the growth of the xenograft tumors over time and retransplanted the tumors if they engrafted.

Results: Our initial data suggested about a take rate of ~35% for the xenografted tumors. Estrogen receptor-positive luminal tumors usually have a very low engraftment rate in immunodeficient mice. However, we observed a relatively high rate of engraftment for luminal tumors.

Conclusions: This new prolactin-humanized mouse model is highly relevant for in vivo exploration of tumor biology and drug response testing of breast cancer, especially for luminal subtypes.
Low abundance protein enrichment for discovery of plasma protein biomarkers for early detection of breast cancer.
Authors: Quong A. A. , Gormley M. , Meng R. , Bhat V. B. , Rosenberg A. L.
Published: February 2017

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Background: Protein biomarkers for breast cancer are desired for early diagnosis, disease prognosis and drug response monitoring. Biomarkers in bodily fluids, such as plasma, allow for non-invasive monitoring and have additional value compared to tissue-based markers. Plasma-based biomarker discovery faces a challenge in that the wide dynamic range of protein concentrations prevents the detection of lower abundance proteins. In this study, we have investigated the use of a novel protein enrichment strategy combined with isobaric label-based LC-MS/MS as well as two experimental designs for the identification of biomarkers of early stage breast cancer.

Methods: Plasma from 12 patients with benign breast lesions and 12 with stage I breast cancer were processed using ProteoMiner enrichment followed by on-bead digestion. Two types of standards were investigated: a pooled standard, consisting of equal portions from the 24 plasma digests and a universal standard. The samples were digested, labeled and analyzed using by HPLC-Chip/Q-TOF analysis. Proteins were identified and quantified using Spectrum Mill software.

Results: Use of ProteoMiner beads resulted in extraction of sufficient protein for at least 10 technical replicates and cut down preparation time by 80%, as compared to MARS-based immunodepletion. A total of 414 plasma proteins were identified, 89% of which are low abundance plasma proteins and 14 of which were differentially expressed. Expression values normalized using the pooled vs. universal standards were significantly correlated.

Conclusions: This study demonstrated use of the ProteoMiner technology for enrichment of low abundance proteins from plasma. Fourteen plasma-based biomarkers of stage I breast cancer were identified with statistical significance. A number of these proteins (e.g., protocadherin FAT2, flightless-1 homolog) have been linked to breast cancer relevant processes, such as cell migration, adhesion, estrogen receptor signaling and proliferation.
Accelerated partial breast irradiation using brachytherapy (APBIb) for breast cancer (bca): Predictors of use and guideline concordance.
Authors: Hattangadi J. A. , Taback N. , Neville B. A. , Harris J. R. , Punglia R. S.
Published: February 2017

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Background: APBIb is a novel alternative to whole breast irradiation (WBI). The American Society for Radiation Oncology Guidelines (ASTRO-G) established appropriateness for APBIb use off protocol.

Methods: 138,815 bca patients from the Surveillance, Epidemiology, and End Results database underwent WBI or APBIb after lumpectomy from 2000 to 2007. Patients were classified as suitable, cautionary, or unsuitable for APBIb according to ASTRO-G. Logistic regression was applied to study APBIb use overall and within each guideline category.

Results: Overall, 2.6% received APBIb and use varied by ASTRO-G: 5% in suitable, 3.4% in cautionary, and 1.6% in unsuitable patients (p<0.0001). APBIb use increased with time (2000: 0.3%, 2007: 7%) and varied widely with region (0% Alaska; 7% Atlanta, Georgia). Independent predictors of APBIb among suitable patients included white (OR 2.0, p<0.001) race, region (OR 2.6-8.6, p<0.0001), later year (2006-7 v 2000-2 OR 20.3, p<0.0001), and lower grade (OR 1.3, p=0.01). Among cautionary patients, white race (OR 1.8, p<0.001), non-Hispanic ethnicity (OR 1.3, p<0.04), region (OR 3.1-10.2, p<0.0001), metropolitan location (OR 1.9, p=0.01), later year (2006-2007 OR 17.6, p<0.0001), and lower grade (OR 1.4, p<0.0001) predicted for APBIb. Among unsuitable patients, race (p<0.0001), region (OR 3.3-21.6, p<0.0001), later year (2006-7 OR 12.7, p<0.0001), estrogen receptor-positive status (OR 1.3, p=0.002), lower grade (OR 1.3, p<0.01), and negative lymph nodes (OR 2.0, p<0.0001) predicted for use. In several regions, odds of APBIb increased as appropriateness decreased (see Table).

Conclusions: APBIb has been rapidly adopted in the US. Its use varied by race, ethnicity, and region, especially among patients who may not be suitable candidates for this technique.

[Table: see text]
Comparing survival with breast-conservation therapy or mastectomy in the management of young women with early-stage breast cancer.
Authors: Mahmood U. , Morris C. G. , Neuner G. A. , Koshy M. , Kesmodel S. , Buras R. , Chumsri S. , Bao T. , Tkaczuk K. H. , Feigenberg S. J.
Published: February 2017

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Background: Previous studies have shown that young women with breast cancer treated with breast-conservation therapy (BCT) experience higher local recurrence rates. Whether such patients are better treated with mastectomy is unclear. The purpose of this study was to evaluate survival outcomes of young women with early-stage breast cancer treated with BCT or mastectomy using a large, population-based database.

Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, information was obtained for all female patients age 20 to 39 diagnosed with T1-2 N0-1 M0 breast cancer between 1990 and 2007 who underwent either BCT (lumpectomy and radiation treatment) or mastectomy. Multivariable analysis as well as a matched pair analysis were performed to compare overall survival (OS) and cause-specific survival (CSS) of patients undergoing BCT and mastectomy.

Results: 14,760 women were identified, of whom 45% received BCT and 55% received mastectomy. Median follow-up was 5.7 years (range: 0.5 to 17.9 years). Multivariable analysis revealed year of diagnosis, age, race/ethnicity, grade, PR status, tumor size, number of lymph nodes positive, and number of lymph nodes examined were independent predictors of OS and CSS while ER status was of borderline significance. After accounting for all patient and tumor characteristics, multivariable analysis found that BCT resulted in similar OS (HR: 0.93; CI: 0.83-1.04; p = 0.16) and CSS (HR: 0.93, CI: 0.83-1.05; p = 0.26) as mastectomy. Matched pair analysis, including 4,644 BCT and mastectomy patients, confirmed no difference in OS or CSS: the 5/10/15-year OS for BCT and mastectomy were 92.5%/83.5%/77.0% and 91.9%/83.6%/79.1%, respectively (p = 0.99) and the 5/10/15-year CSS for BCT and mastectomy were 93.3%/85.5%/79.9% and 92.5%/85.5%/81.9%, respectively (p = 0.88).

Conclusions: Young women with early-stage breast cancer have equivalent survival whether treated with BCT or mastectomy. These patients should be counseled appropriately regarding their treatment options, and should not choose a mastectomy based on the assumption of improved survival.
Effect of serial sectioning and immunohistochemistry (IHC) on sentinel lymph nodes (SLNs) on the false-negative rate (FNR) of SLN biopsy (SLNB): Results from NSABP B-32.
Authors: Mamounas E. P. , Anderson S. J. , Julian T. B. , Krag D. N. , Weaver D. , Ashikaga T. , Harlow S. P. , Wolmark N.
Published: February 2017

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Background: In NSABP B-32 5611 women with invasive breast cancer were randomly assigned to SLNB plus axillary dissection or SLNB alone. Permanent pathologic assessment of SLNs at participating sites was designed to identify all macrometastases >2 mm (slicing SLNs at approximately 2.0 mm intervals, embedding all slices in paraffin tissue blocks, and examining one H&E-stained slide from each block). Routine use of IHC or deeper sectioning was prohibited. SLN paraffin tissue blocks from negative SLNs were later evaluated centrally for occult metastases deeper in the blocks. In this report we examine the effect of this detailed assessment on the FNR of SLNB.

Methods: Routine and cytokeratin IHC stains were used at two widely spaced additional levels. Occult metastases were detected in 616 of 3884 pts (15.9%) with initially negative SLNs; 69.8% had isolated tumor-cells, 27.9% micrometastases, and 2.3% macrometastases (Weaver D, et al: N Engl J Med, 2011).

Results: Previously reported FNR in B-32 was 9.8% (75 of 766 pts). Information on additional pathologic assessment was available on 72 of these 75 pts and revealed occult metastases in 23 pts (31.9%). Of those 23 pts, 14 had isolated tumor cells (61%), 7 had micrometastases (30%), and 2 had macrometastases (9%) in the SLN. Including the information from the additional pathologic assessment, the FNR of SLNB in B-32 was reduced to 6.4% (49 of 763 cases). This 35% reduction in FNR was statistically significant (p< 0.001). Among the 23 FN SLNs with occult metastases, the number of positive non-SLNs was 1 in 16 pts, 2 in 2 pts, 3 in 2 pts, 4 in 2 pts, and 6 in 1 pt.

Conclusions: In the B-32 trial, more detailed assessment of the SLNs with deeper sectioning and IHC staining would have significantly reduced the FNR of SLNB by about one-third. However, this reduction would have come at the expense of a 16% increase in the rate of axillary dissection by taking occult metastases into account. Supported by NCI: U10-CA-12027, U10-CA-37377, U10-CA-69974, U10-CA-69651; and ARRA ROI CA 74137.
Genome-wide copy number analysis of circulating tumor cells from patients (pts) with metastatic breast cancer (MBC).
Authors: Magbanua M. J. M. , Sosa E. , Roy R. , Eisenbud L. , Scott J. , Olshen A. , Pinkel D. , Rugo H. S. , Park J. W.
Published: February 2017

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Background: We developed a novel approach to isolate circulating tumor cells (CTCs) via immunomagnetic enrichment followed by fluorescence activated cell sorting (IE/FACS) and examined copy number alterations in these cells.

Methods: Magnetic beads coated with EpCAM mAb were added to blood to enrich for tumor cells. Enriched samples were then subjected to FACS analysis using differentially labeled mAbs to distinguish tumor cells (EpCAM+) from leukocytes (CD45+) during sorting. DNA from isolated tumor cells was subjected to whole genome amplification (WGA) and copy number analysis via array comparative genomic hybridization (aCGH). The assay was evaluated in CTCs from 5 MBC pts with matched archival primary tumors and later extended to an additional 176 MBC pts, 97 of which were successfully profiled.

Results: Comparison of CTCs with matched archival primary tumors confirmed shared lineage with notable divergence. In addition, serial testing of CTCs confirmed reproducibility, and indicated genomic change over time. Genomic profiling of CTCs from 102 MBC pts revealed a wide range of copy number alterations including those previously reported in breast cancer. Comparison with a published aCGH dataset of primary breast tumors revealed similar frequencies of recurrent genomic copy number aberrations.

Conclusions: It is feasible to isolate CTCs away from hematopoietic cells with high purity via IE/FACS and profile them via aCGH analysis following WGA. Our approach may be utilized to explore genomic events involved in cancer progression and to monitor therapeutic efficacy of targeted therapies in clinical trials in a relatively non-invasive manner. This work was supported by grants from the CALGB, BCRF, TBCRC (Avon, Komen), EDRN and U54.