bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-04-01: Breast milk exosomes promote breast cancer progression
Authors: Sauter ER , Qin W , Dasgupta S
Published: May 2016

Background: The stimulation of extant neoplastic cells vs. their inhibition during breast involution is a key concept in whether pregnancy and lactation decrease or increase breast cancer risk. The time of weaning, a period of breast involution and remodeling, appears critical to future breast cancer risk, as during involution the breast microenvironment becomes tumor promotional. Both matrix metalloproteinases (MMPs) and transforming growth factor (TGF)β isoforms have been implicated in this process. We previously reported that TGFβ2 (but not TGFβ1) expression was significantly higher in milk collected from the cancer containing (vs. matched clinically normal) breast of women diagnosed with cancer during lactation.

Hypothesis: TGFβ2 in milk exosomes from healthy lactating women modulates the development and progression of breast cancer.

Methods: Matched (early, mature and wean-early involution) milk samples were collected from 13 lactating women, exosomes isolated and the levels of five (MMP2, 3, 9; TGFβ1, 2) proteins measured. Based on the results, additional wean samples were analyzed for TGFβ2 expression and samples divided based on their TGFβ2 expression. The highest and lowest TGFβ2 expressing milk exosome samples were co-cultured with MCF-7 breast cancer cells grown in exosome-depleted media. Cell proliferation was measured after 24h. Confocal microscopy was performed after 72h to evaluate epithelial to mesenchymal transition (EMT) in the cells. A TGFβ2 neutralizing blocking antibody was applied after 72 h co-culture.

Results: The greatest increase in expression (four-fold) at the time of involution was in TGFβ2. Confocal microscopy performed 24h after co-culture confirmed the uptake of the exosomes (both those expressing hi and lo TGFβ2) in the MCF-7 cells. There was a significant increase in cell proliferation compared to control (p<0.001) in cells treated with hi TGFβ2 milk exosomes. 72h after co-culture, bright field microscopy demonstrated that MCF-7 cells treated with hi TGFβ2 underwent EMT including the formation of filopodia, whereas those treated with low TGFβ2 did not. A TGFβ2 blocking antibody reversed the EMT phenotype and filopodia formation.

Impact: Pregnancy has a lasting influence on breast cancer risk, and pregnancy associated breast cancers (PABCs) diagnosed after delivery are generally aggressive, with a poor prognosis. Part of the reason for the development of PABCs, and the aggressive nature of PABCs may be the influence of high-expressing TGFβ2 exosomes in the milk on the breast ductal epithelium.

Citation Format: Sauter ER, Qin W, Dasgupta S. Breast milk exosomes promote breast cancer progression. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-04-01.
Abstract P1-05-02: The N-terminus of Twist1 is responsible for interacting with transcriptional repressors to promote EMT and metastasis of breast cancer cells
Authors: Yu X , He T , Xu J
Published: May 2016

Twist1, a basic helix-loop-helix transcription factor, plays a key role to mediate epithelial-mesenchymal transition (EMT) and promote breast cancer metastasis. However, knowledge about Twist1 structure-function relationships to cancer-related phenotypes is limited. Therefore, we studied the requirement of Twist1 N-terminus in Twist1-dependent breast cancer metastasis. We showed that the amino-terminus of Twist1 was the dominant negative mutant of Twist1. Overexpression of Twist1 N-terminus exhibited different cell morphology and motility in vitro. Inoculation of Twist1 N-terminus overexpression cells into SCID mice showed delayed tumor formation and reduced lung metastasis. Furthermore, Twist1 N-terminus overexpression induced expression change of EMT markers, including E-cadherin, β-catenin, vimentin and Twist1 both in vivo and in vitro. Co-immunoprecipitation and mass spectrometry revealed that Twist1 N-terminus interacted with several members of the Mi2/nucleosome remodeling and deacetylase (Mi2/NuRD) complex, HDAC2, 3 and 7, MTA1 and 2, RbAp46/48, and many corepressors including NCoR1 and 2, which released them from the proximal region of E-cadherin promoter for transcriptional activation. These data suggest that Twist1 N-terminus is required for Twist1-mediated transcriptional programs and breast cancer metastasis.

Citation Format: Yu X, He T, Xu J. The N-terminus of Twist1 is responsible for interacting with transcriptional repressors to promote EMT and metastasis of breast cancer cells. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-05-02.
Abstract P1-06-04: Bisphenol A treatment induces hyperplasia in primary and stem cell-generated mammary glands from pregnant mice
Authors: Bouamar H , Zhang F , Gu X , Dong Q , Sun L-Z
Published: May 2016

Breast cancer is a commonly diagnosed cancer of pregnancy. However, how endogenous and exogenous endocrine factors may contribute to the development of pregnancy-associated mammary tumorigenesis is not clear. There is growing evidence that mammary stem cells (MaSCs) may initiate neoplastic transformation when dysregulated in mouse models. We investigated the effect of the environmental endocrine disruptor bisphenol A (BPA) on mouse mammary gland morphology, epithelial cell composition, pre-neoplastic lesions, and the regenerative function of MaSCs. Pregnant FVB mice with GFP transgene on Day E8.5 were implanted with osmotic pumps that constantly release BPA at 0, 25 or 250 ng/kg/day for 28 days and the mice were euthanized one month after weaning. In agreement with the literature, we observed an abnormality of the morphology of the mammary gland after BPA treatment characterized by higher duct density and abnormal secondary and tertiary branching. Quantification of percent hyperplastic mammary ducts in H&E-stained tissue slides revealed a significant increase of ducts with hyperplastic lesions after BPA treatment, particularly with the low dose. To investigate the effects of BPA treatment on MaSCs, we used enzyme digestion to isolate the CD24hi/CD49f+ luminal epithelial cells (also termed as colony forming cell or CFC) and the CD24+/CD49fhi basal epithelial cells (also termed as mammary repopulating unit or MRU) from mammary gland tissues by FACS and found no significant difference in percent of luminal or basal cell population after BPA treatment. Because the basal cells are enriched with MaSCs that can form mammospheres in suspension culture and subsequently form solid 3D organoids when cultured in Matrigel, we transplanted the solid 3D organoids into cleared mammary fat pads of syngeneic FVB mice and immune-compromised nude mice to examine how BPA treatment might alter MaSC function. Significantly, similar to the results from the primary mammary glands, the regenerated mammary glands by MaSCs from mice treated with the low dose of BPA showed increased duct density, secondary and tertiary branching, and a significantly greater number of hyperplastic lesions. Taken together, our study demonstrated that BPA exposure at very low dose could induce pre-neoplastic lesions in the mammary gland of pregnant mice, apparently by directly targeting MaSCs and implicates BPA as an exogenous endocrine factor that may promote pregnancy-associated mammary tumorigenesis.

Citation Format: Bouamar H, Zhang F, Gu X, Dong Q, Sun L-Z. Bisphenol A treatment induces hyperplasia in primary and stem cell-generated mammary glands from pregnant mice. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-06-04.
Abstract P1-06-07: Msi1 in maintaining breast cancer stem cell involves the AKT/PI3K pathway
Authors: Nahas GR , Sinha GA , Sherman LS , Walker ND , Rameshwar P
Published: May 2016

Musashi1 (Msi1) was originally described in neural stem cells in a role influencing neural differentiation in the Numb/Notch pathway. Due to its role in neural stem cells, there has been much interest in the role of Msi1 in the breast cancer (BC) stem cell population. In this vein, with we have demonstrated a possible feedback loop between the stem cell marker OCT4 and Msi1, in addition to other stem cell-associated genes. Flow cytometry analyses demonstrated that the subset of BC cells (BCCs) that we previously identified as those with high Oct4 was also enriched for Msi1. Msi1 knockdown BCCs showed decreased doubling time and with limited ability to be passaged, indicating the loss of the self-renewal subset needed for cell passaging. These in vitro findings were consistent with the inability of the Msi1 knockdown BCCs to undergo serial passages in vivo. We therefore examined the Msi1 knockdown BCCs for intracellular proteins that could explain the reduced cell growth and the reduced initiating cells. We selected the AKT/PI3K pathway due to its recent connection to the maintenance of BC stem cells. Msi1 knockdown repressed several molecules within the AKT/PI3K pathway: PTEN, AKT, and PI3K. There were no significant differences found however, in the apoptotic factors, BCL-2 and Caspase-3. Upon further investigation, we observed increases in molecules that are linked to decreased cell proliferation and senescence, p16, p53 and p21. Since Msi1 is an RNA binding protein, it is possible that its loss could leave RNAs for binding to miRNAs and this might be partly responsible for the decrease in key intracellular molecules needed for the survival and proliferation of the Msi1 knockdown BCCs. Further studies are needed to investigate how miRNAs and Msi1 interact to maintain the survival of BCCs. Finally, Msi1 KD positively affects the expression of the immune checkpoint inhibitor PD-1L, suggesting increased PD-1L expression in cells that are not of the CSC phenotype. The studies may identify Msi1 or its associated molecules as a potential therapeutic intervention for BC.

Citation Format: Nahas GR, Sinha GA, Sherman LS, Walker ND, Rameshwar P. Msi1 in maintaining breast cancer stem cell involves the AKT/PI3K pathway. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-06-07.
Abstract P1-07-10: Increasing population rates of in-situ breast cancer [DCIS] are associated with reduced breast cancer (BrCa) mortality. A case for screening mammography and "overdiagnosis" linked to outcome benefits
Authors: Ragaz J , Qian H , Shakeraneh S , Fox J , Wilson KS , Simpson JS , Yoon J-Y , Wong H
Published: May 2016

INTRODUCTION:

Following the first phase of this project [Ref 1], we correlate here the rates of DCIS with BrCaMOR, in two regions of Canada - British Columbia [BC] and Atlantic Provinces [Atl.P].

We previously reported higher compliance in screening mammography [ScreenMam] and therapeutic [TH*] guidelines [GUIDELINES] for both DCIS and invasive BrCa in BC compared with Atl.P [Ref. 2].

METHODS: Annual age-specific rates [cases / 100,000 population] of DCIS, and BrCaMOR between BC vs Atl.P, were obtained for 17 age groups of 5 years (years 0-4 to 85+) and averaged each 5-year period from 1975-1979 up to 2005-2009. To compare age distribution, DCIS rates and BrCaMOR between the two regions, we selected four birth cohorts, age 30-34, 35-39, 40-44 and 45-49 in 1975-1979. From those, we tabulated the DCIS incidence and BrCaMOR for each birth cohort when they reached ages 50-54 and 60-64. We assumed that the rates of DCIS reflect annual ScreenMam practices.

Data were obtained from the Public Health Agency of Canada based on the Canadian Cancer Registry database at Statistics Canada.

RESULTS [N/100,000 population]British ColumbiaAtlantic ProvincesAge / years DCISBrCaMORDCISBrCaMORAge 50 â– 54  1980-8413.152.24.056.41985-8921.246.68.056.11990â–9429.244.421.449.91995â–9945.543.830.050.1Age 60â – 64  1990-9428.072.123.186.21995-9949.361.935.276.62000-0449.365.845.669.42005â–0951.453.141.059.4

CONCLUSIONS:

1. Our study shows across all age cohorts higher rates of DCIS and lower BrCaMOR in BC compared to Atl.P - results consistent with higher ScreenMam rates in BC than Atl.P.

2. These data are compatible with the concept that a higher diagnostic rate for early lesions such as DCIS [i.e. frequently designated as "Overdiagnosis"] by ScreenMam, and subsequent earlier Guideline TH*, contributes to lower BrCaMOR.

*TH Guidelines: surgery, radiation, Tamoxifen for DCIS; and the same + chemotherapy for early invasive disease.

Citation Format: Ragaz J, Qian H, Shakeraneh S, Fox J, Wilson KS, Simpson JS, Yoon J-Y, Wong H. Increasing population rates of in-situ breast cancer [DCIS] are associated with reduced breast cancer (BrCa) mortality. A case for screening mammography and "overdiagnosis" linked to outcome benefits. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-10.

References:

1. J. Ragaz, H. Wong, H. Qian, J.Fox, K. Wilson, A. Coldman: Cancer Research, May 1, 2015 75; P3-07-28

2. J. Ragaz, H. Wong, H. Qian: Cancer Research Feb 2010; 69(24 Supplement):2063-2063.
Abstract P1-07-17: Breast cancer presentation in the over 70s
Authors: Murray J , Smith L , Lannigan A
Published: May 2016

Aims:

Life expectancy of the population in rising, and the risk of breast cancer increases with age. Older patients with breast cancer generally present later with more advanced disease for a variety of factors. We aimed to explore the presentation of the over 70s with breast cancer, along with their attitudes towards screening.

Methods:

A questionnaire was sent to patients aged over 70 at the time of their breast cancer surgery within the three hospitals across NHS Lanarkshire. This detailed reasons and timing of presentation, in addition to thoughts about screening.

Results:

Three hundred and fifty-two questionnaires were sent to women with a mean age of 76 years, 230 were returned (65%). Sixty-four percent routinely examined their breasts with more identifying a lump themselves (70%). Knowledge of signs and symptoms beyond a lump was explored, explicitly asking about nipple inversion, nipple discharge and skin changes with all three having similar degrees of awareness (40%, 35%, 25% respectively). Distressingly only 36% of our patients were aware of any of these signs, with only 9% being aware of all three. The majority of women sought medical attention early after identifying a problem, with 39% seeing someone within days and only 6% waiting over 6 months. Personal concern was the greatest prompt for women to see a doctor (68%) followed by family or friend concern (10%). With regard to screening, 83% routinely attended screening when they were invited. Ninety percent also said they would attend if the service was routinely offered to the over 70s. Although the majority (60%) were not aware that they could opt into the screening service once over 70.

Conclusions:

Despite the belief that most older women are felt to be less breast aware than younger most of our patients routinely examined themselves and identified the pathology, before promptly seeking medical advice (70% within weeks). This is the case despite most women having no knowledge of other signs and symptoms of breast cancer. Our cohort have also shown that they are keen to continue screening over the age of 70 if it was routinely offered.

Citation Format: Murray J, Smith L, Lannigan A. Breast cancer presentation in the over 70s. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-17.
Abstract P1-07-23: Prognostic impact of HER2 overexpression/amplification in women with pT1a N0 M0 breast cancer with known screening status: Results from a multicenter population-based cancer registry study
Authors: Musolino A , Michiara M , Boggiani D , Sikokis A , Rimanti A , Pellegrino B , Silini EM , Campanini N , Barbieri E , Sgargi P , Falcini F , Pinto C
Published: May 2016

Introduction: Outcomes for women with pT1aN0M0 breast cancers (BC) may vary by biologic subtype. A higher proportion of HER2-positive BCs diagnosed in the interval between scheduled screening rounds has been proposed to account for the more aggressive behaviour of interval cancers (IC) compared with screen-detected (SD) tumors. No data are available on the prognostic role of HER2-positive status in a general population of pT1aN0M0 breast tumors with known screening status.

Methods: All incident pT1aN0M0 BCs (n=874), systematically collected by the Cancer Registries of Emilia Romagna Region (northern Italy) and diagnosed in women aged 50-69 from 2003 to 2009 were evaluated. Screening status was ascertained by reference to the Emilia Romagna Breast Cancer Screening Program (ERBSP) database. Patients unexposed to screening, with HER2 unknown primary tumor and/or who received adjuvant chemotherapy or trastuzumab were excluded from analysis.

Results: Twenty percent of patients had HER2-positive tumors. Fifty-three percent of the entire study population were SD cancers, while 18% were ICs. Tumors with high histologic grade, high proliferative rate, negative estrogen receptor status, or HER2-positive status were more likely to be diagnosed in the interval between screening. At a median follow-up of 84 months, the 5-year invasive disease-free survival (IDFS) rates were 89% and 95% in patients with HER2-positive and HER2-negative tumors, respectively (P = 0.025). Notably, HER2-positive ICs showed poorer IDFS than HER2-positive SD tumors (84% vs. 95%, respectively; P = 0.04). No difference in IDFS rates were observed between HER2-positive SD cancers and HER2-negative SD cancers. Multivariable analysis of candidate prognostic factors for IDFS will be reported.

Conclusions: In a general population of pT1aN0M0 early BCs with known screening status, IC detection may identify patients with HER2-positive pT1aN0M0 tumors in whom the rate of recurrence justifies consideration for systemic, anti-HER2, adjuvant therapy.

Citation Format: Musolino A, Michiara M, Boggiani D, Sikokis A, Rimanti A, Pellegrino B, Silini EM, Campanini N, Barbieri E, Sgargi P, Falcini F, Pinto C. Prognostic impact of HER2 overexpression/amplification in women with pT1a N0 M0 breast cancer with known screening status: Results from a multicenter population-based cancer registry study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-23.
Abstract P1-08-03: Association analysis of single-nucleotide polymorphisms in FANCD2-DNA damage repair pathway genes with breast cancer risk
Authors: Chen F , Tang L , Huang J
Published: May 2016

Purpose: The aim of the study was to estimate breast cancer risk conferred by individual single-nucleotide polymorphisms (SNPs) of breast cancer susceptibility genes in the monoubiquitinated FANCD2–DNA damage repair pathway.

Methods: We selected 48 tagging SNPs (tSNPs) from eight breast cancer susceptibility genes (TP53,PTEN,NBS1,BRIP1,PALB2,ATM,CHEK2 and RAD50) involved in the monoubiquitinated FANCD2–DNA damage repair pathway.The 48 tSNPs were genetyped by SNPscan in 734 women with breast cancer(534 sporadic cases and 200 early-onset and familial cases) and 672 sex- and age-matched healthy controls from Hunan and Sichuan Province of China.The odds ratio were calculated by logistic regression analysis under co-dominant model ,dominant model and recessive model respectively.

Results: Forty-five tSNPs were successfully genotyped by SNPscan, and the call rates for each tSNP were above 98.9%. We found that 13 tSNPs of five genes (PALB2, TP53, NBS1, PTEN, and BRIP1) were significantly associated with breast cancer risk. A total of five tSNPs (rs2299941 of PTEN, rs2735385, rs6999227, rs1805812, and rs1061302 of NBS1) were tightly associated with breast cancer risk in sporadic cases, and five other tSNPs (rs1042522 of TP53, rs2735343 of PTEN, rs7220719, rs16945628, and rs11871753 of BRIP1) were tightly associated with breast cancer risk in early-onset and familial cases. We have not found significant tSNPs in the other three genes (ATM, RAD50, and CHEK2).Three tSNPs of TP53(rs12951053, rs1042522 and rs8064946),three tSNPs of BRIP1(rs16945628, rs7220719 and rs11871753) and rs2735343 of PTEN can significantly increase the risk of breast cancer,and most of these were under the analysis of early-onset and familial cases.Four tSNPs of NBS1(rs2735385, rs6999227, rs1805812 and rs1061302),rs2299941 of PTEN and rs513313 of PALB2 can significantly decrease the risk of breast cancer,and most of these were under the analysis of sporadic cases.

Conclusions: Some of the tSNPs of five breast cancer susceptibility genes (PALB2, TP53, NBS1, PTEN, and BRIP1) involved in the monoubiquitinated FANCD2–DNA damage repair pathway were significantly associated with breast cancer risk in women from Hunan and Sichuan Province of China.Some locuses can increase breast cancer risk,and others can decrease breast cancer risk.But the majority of the tSNPs are located in the intron domain and their functions are unknown, so larger studies are needed to research the functions of these genes further.

Citation Format: Chen F, Tang L, Huang J. Association analysis of single-nucleotide polymorphisms in FANCD2-DNA damage repair pathway genes with breast cancer risk. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-08-03.
Abstract P1-08-08: Heterozygous germline mutations in RAD50 among Korean patients with high-risk breast cancer negative for BRCA1/2 mutation
Authors: Kim H , Cho D-Y , Choi DH , Jung GH , Shin I , Park W , Huh SJ , Nam SJ , Lee JE , Gil WH , Kim SW
Published: May 2016

Background: The MRE11-RAD50-nibrin (MRN) complex participates in pathways of double-strand break induced DNA repair and cell cycle checkpoint control. RAD50 interacts with the MRE11 and NBS proteins, is involved in the maintenance of genomic integrity. The association of RAD50 mutation and breast cancer susceptibility has been reported in European patients. However, the impact of RAD50 mutation on a breast cancer predisposition among Koreans remains uncertain. In the current analysis, we evaluated the incidence of RAD50 mutations among Korean patients with non-BRCA1/2 high-risk breast cancer.

Materials and Methods: A total of 247 Korean patients with high-risk breast cancer who tested negative for BRCA1/2 mutation were enrolled. The criteria for high-risk breast cancer were as follows: having a family history of breast or ovarian cancer in any relative; diagnosed at age 40 years or younger; bilateral breast cancer; and male breast cancer. All participants were screened for BRCA1/2 mutations using fluorescent-conformation sensitive capillary electrophoresis (F-CSCE) and traditional sequencing. The entire RAD50 gene of each patient was sequenced using F-CSCE. In silico analyses of the RAD50 variants was performed using PolyPhen-2 and SIFT.

Results: There were two novel deleterious mutations in RAD50 (p.Q426X, p.E1271del). These mutations were found in two patients, including one with p.Q426X and the other with p.E1271del. Besides, five sequence variants in RAD50 were identified: four exonic variants (p.I118T, p.R486C, p.L1264F, and p.R1279H) and one intronic variant (c.1246-11T>C). Among the four missense variants, p.R486C and p.L1264F were variants predicted to be deleterious by in silico analyses.

Conclusions: We found protein-truncating mutations in RAD50 gene in a small proportion of Korean patients with high-risk breast cancer. The contribution of the mutation to the development of breast cancer should be clarified in further researches.

Citation Format: Kim H, Cho D-Y, Choi DH, Jung GH, Shin I, Park W, Huh SJ, Nam SJ, Lee JE, Gil WH, Kim SW. Heterozygous germline mutations in RAD50 among Korean patients with high-risk breast cancer negative for BRCA1/2 mutation. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-08-08.
Abstract P1-10-19: Skin, and nail, infections associated with the addition of pertuzumab to trastuzumab-based chemotherapy
Authors: Mortimer JE , Yuan Y , Jung J , Kruper L , Stewart D , Chung S , Yu WK , Mendelsohn M , D'Apuzzo M , Tegtmeier B , Dadwal S
Published: May 2016

Objectives: We have maintained a local registry of skin and nail infections in patients receiving pertuzumab and trastuzumab as treatment for HER2 positive breast cancer. Over the past 16 months, we have continued to observe an increase in infectious complications in patients receiving the combination of pertuzumab and trastuzumab with or without chemotherapy. We expand a series of prospectively identified patients who developed infections while on these regimens. Methods: We became concerned about an increased incidence of infections shortly after the FDA approval of pertuzumab, and created an IRB approved registry of these patients. Results: Twenty-eight women were identified to have 32 separate infections (often at more than one site); 9 after cycle 1; 6 after cycle 2, 9 after cycle 3 and 8 after 4 or more cycles. The median age was 51 (Range 25-67); 14 received pertuzumab, trastuzumab, carboplatin, and docetaxel (PTCH), 5 pertuzumab, trastuzumab, and docetaxel, 7 pertuzumab, trastuzumab, and nab-paclitaxel, and 2 pertuzumab and trastuzumab. Folliculitis of the scalp, abdomen, and/or buttocks was observed in 19 patients, abscesses in 8 patients (4 of whom required incision and drainage) and cellulitis in 2. Severe paronychial infections involving one to 16 digits were observed in 4; 2 pt required surgical removal of 2 nails. Quantitative immunoglobulins were found to be low in 8 of 17 women tested; 2 patient had low total protein but did not have an assessment of quantitative immunoglobulins. All patients were initially treated with oral antibiotics, and 6 required hospitalization. Cultures were obtained in 10 patients; Staphylococcus aureus was identified in 4, methicillin resistant Staphylococcus aureus (MRSA) in 5, Enterococcus faecalis in 1. A 57 year old pt receiving neoadjuvant PTCH died on cycle 2 day 7. Autopsy was consistent with sepsis and gram positive cocci were identified. A 62 year old became septic and developed renal failure. Skin biopsies were performed in 3 patients and are consistent with changes associated with EGFR inhibition.

Conclusions: We believe these infections are a result of combining pertuzumab with trastuzumab as 2 pts received no concurrent chemotherapy. An awareness of this complication is critical as some infections may be life-threatening. We have initiated patient education to ensure awareness of this potential complication.

Citation Format: Mortimer JE, Yuan Y, Jung J, Kruper L, Stewart D, Chung S, Yu WK, Mendelsohn M, D'Apuzzo M, Tegtmeier B, Dadwal S. Skin, and nail, infections associated with the addition of pertuzumab to trastuzumab-based chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-19.
Abstract P1-10-25: Intrathoracic paclitaxel chemotherapy for malignant pleural effusion in breast cancer
Authors: Yeu KJ , Park J , Choi JE , Kang SH , Lee SJ
Published: May 2016

Background: Malignant pleural effusion in breast cancer has been associated with poor prognosis which median survival rate is 5–16 months. The response rate of local treatment has been very low and in some case, complications have resulted in death.

Patients and methods: We investigated the efficacy and safety of paclitaxel, as an intrapleural chemotherapeutic agent. From January 2006 to June 2015, total 35 times of intrapleural chemothepapy were performed in 26 breast cancer patients who had developed malignant pleural effusion. They were infused 120mg/m2 of paclitaxel through a chest tube, which was clamped for 48 hours. The chest tube was maintained until drainage was reduced to less than 50-100 mL/day.

Results: Mean follow up period after intrapleural chemotherapy was 11 months.The average time of indwelling with a chest tube after intrapleural chemotherapy was 9.7 days.

Mean progression free survival was 7.8 Months. During the follow-up period, 5 patients had no progression of pleural effusion and 2 of them were free from progression for more than 36 months. In 26 attempts, there were effective and could remove chest tube otherwise In 9 attempts, there were no improvement after intrapleural chemotherapy. 1 patients received a second round of ipsilateral intrapleural chemotherapy and had no response unlike earlier attempts. There were 3 severe adverse effect related death caused by respiratory failure with or without G4 neutropenia.

Conclusion: Intrapleural paclitaxel chemotherapy is helpful for some cases of uncontrolled pleural effusion in that reduce the duration of hospital stay and improve quality of life. But it will be determined carefully, considering the side effects and response rate of treatment.

Citation Format: Yeu KJ, Park J, Choi JE, Kang SH, Lee SJ. Intrathoracic paclitaxel chemotherapy for malignant pleural effusion in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-25.
Abstract P1-10-26: Frozen glove could be a new hope for prevention of chemotherapy induced peripheral neuropathy
Authors: Nakayama T , Yasojima H , Morimoto T , Yoshidome K , Mizutani M , Takashima T , Matsunami N , Enami A , Kagawa M , Nomura T , Shiba E , Nishi T , Kamigaki S , Kozuma Y , Yoshinami T , Masuda N
Published: May 2016

Introduction

Chemotherapy induced peripheral neuropathy (CIPN) is a major problem for patients who receive chemotherapy, and it sometimes deteriorate patients' QOL. Many CIPN prevention trials have been conducted, but no one succeeded to date.

Objectives

To investigate if frozen glove (FG) prevents peripheral neuropathy induced by nanoparticle albumin-bound paclitaxel (nab-PTX).

Methods

We conducted CIPN prevention study using FG, as part of multi-institutional phase II study which analyze efficacy and safety of nab-PTX (260mg/m2 q3w) followed by FEC (500/100/500 mg/m2, q3w) in pre-operative setting (KBCSG-TR 1213 trial). Each patient wore an FGs for a total of 60 minutes (15mins before and after nab-PTX treatment) on both hands. CIPN were assessed during treatment period with nab-PTX by the Patient Neurotoxicity Questionnaire (PNQ) and the FACT/GOG (Gynecologic Oncology Group) Neurotoxicity (Ntx) subscale. Patients were asked to access PNQ and FACT/GOG Ntx on a daily basis and recorded in the CIPN diary.

Results

Sixty two patients were registered for KBCSG-TR 1213 trial. And forty two pts (68%) who turned in the diary were analyzed. Median age and median body mass index (BMI) was 48 years old and 21.6 kg/m2, respectively. We analyzed following 6 categories, 1) symptoms of hands and arms, 2) symptoms of foots, 3) symptoms of general, 4) symptoms of ears 5) muscle weakness of hands and arms and 6) muscle weakness of foots. Median time to each event was 1) 25.5 days, 2) 5days, 3) 3days, 4) not available, 5) 46.5days, 6)4 days. By using FG, time to event of hands and arms was much longer compared with that of foots.

Conclusions

CIPN could be prevented or lessened by FG. Randomized phase II CIPN prevention study has been just launched.

Citation Format: Nakayama T, Yasojima H, Morimoto T, Yoshidome K, Mizutani M, Takashima T, Matsunami N, Enami A, Kagawa M, Nomura T, Shiba E, Nishi T, Kamigaki S, Kozuma Y, Yoshinami T, Masuda N. Frozen glove could be a new hope for prevention of chemotherapy induced peripheral neuropathy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-26.
Abstract P1-11-02: Psychological morbidity in breast cancer survivors: Prevalence rates and determinants
Authors: Hubalek M , Sztankay M , Oberguggenberger A , Meraner V , Egle D , Mangweth-Matzek B , Beer B , Huber N , Sperner-Unterweger B
Published: May 2016

Background: The number of breast cancer survivors (BCS) is steadily increasing due to improved treatment options, early detection and younger age at diagnosis. Thus, it is increasingly important to determine and better understand the psychological outcome following a cancer diagnosis and treatment in long-term. This might contribute to meeting the long-term health care demands of cancer survivors. We aimed at investigating levels and determinants of anxiety and depression (AD) in BCS.

Patients and Methods: We included BCS with a non-metastatic disease in the stage of after-care. AD was determined as part of a cross-sectional, comprehensive patient reported outcome (PRO) assessment (incl. Functional Assessment of Cancer Therapy-G/+B/+ES, Eating Disorder Examination-Questionnaire, Sexual Activity Questionnaire and Body Image Scale) using the Hospital Anxiety and Depression Scale (HADS). Prevalence rates of AD and sample characteristics are presented descriptively using percentages, means and standard deviations. Predictors of anxiety and depression are identified by means of regression analysis.

Results: A final sample of 743 breast cancer survivors who were on average 2.9 years post diagnosis (range: 0.1-11.3 years) participated in the study. Mean patient age was 56.4a (SD 11.5a), 2/3 of patients were postmenopausal. 22.5% of patients reported clinically relevant levels of anxiety and 11.2% of depression. Older age (β=0.012, t=2.53, p<0.05), higher endocrine symptoms (β=-0.037, t=-8.89, p<0.01) and reduced functional well-being (β=-0.034, t=-7.73, p<0.01) were predictive for anxiety and depression in the regression model. The model explained 39.3% of the variance of anxiety and depression.

Conclusion: A distinct proportion of BCS report clinically relevant, long-term psychological morbidity. Especially older BCS, experiencing higher levels of endocrine symptoms and reduced functional well-being, seem to be at risk for psychological morbidity. A routine PRO-screening for psychological morbidity including the assessment of associated risk factors in this patient population might contribute to the identification of those women in need for psychological/ psychiatric treatment and in conjunction, improve cancer care.

Citation Format: Hubalek M, Sztankay M, Oberguggenberger A, Meraner V, Egle D, Mangweth-Matzek B, Beer B, Huber N, Sperner-Unterweger B. Psychological morbidity in breast cancer survivors: Prevalence rates and determinants. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-11-02.
Abstract P1-14-02: Disease-free (DFS) and overall survival (OS) data from ACOSOG Z1041 (Alliance) a randomized neoadjuvant trial comparing FEC followed by paclitaxel plus trastuzumab (FEC → P+T) with paclitaxel plus trastuzumab followed by FEC plus trastuzumab (P+T → FEC+T) in HER2-positive operable breast cancer
Authors: Buzdar AU , Suman VJ , Meric-Bernstam F , Leitch AM , Ellis MJ , Boughey JC , Unzeitig GW , Royce ME , Ewer MS , Hunt KK
Published: May 2016

Background

ACOSOG Z1041 (Alliance) found pathological complete response rates in women with operable HER2-positive breast cancer were similar with FEC → P+T (Arm 1) and P+T → FEC+T (Arm 2) where treatment was administered as 5-FU 500 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 day 1 of a 21-day cycle x 4; paclitaxel 80 mg/m2 weekly x 12 and trastuzumab 4 mg/kg once then 2 mg/kg weekly x 11. We now report DFS and OS results with a median follow up of 4.4 years (range: 26 days to 6.2 years).

Methods

All patients who began study treatment were included in the analyses. Stratified log rank tests and stratified proportional hazard models were used to assess differences in DFS and OS from randomization between treatment arms.

Results

From September 15, 2007 to December 15, 2011, 282 women with HER2-positive breast cancer were enrolled. Two patients randomized to arm 1 withdrew consent prior to treatment and are excluded from these analyses. Patient and disease characteristics of the remaining 280 women (arm 1, n=138; arm 2, n=142) were similar between treatment arms. Recurrences and deaths are shown in the table. DFS were not found to differ with respect to treatment arm (stratified logrank p=0.6870; HR stratified (Arm2/Arm1)=0.88; 95%CI: 0.48-1.61). Also, OS was not found to differ with respect to treatment arm (stratified logrank p=0.8790; HR stratified (Arm2/Arm1)=1.07; 95%CI: 0.43-2.69).

Conclusions

Concurrent administration of trastuzumab with anthracyclines offers no additional benefit in terms of achieving pathologic complete response or improving survival and is not needed.

 FEC → P+TP+T → FEC+T Arm 1Arm 2n138142Recurrences2022Deaths811

Grant Support: U10 CA76001

The study is registered with ClinicalTrials.gov, number NCT00513292.

Citation Format: Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig GW, Royce ME, Ewer MS, Hunt KK. Disease-free (DFS) and overall survival (OS) data from ACOSOG Z1041 (Alliance) a randomized neoadjuvant trial comparing FEC followed by paclitaxel plus trastuzumab (FEC → P+T) with paclitaxel plus trastuzumab followed by FEC plus trastuzumab (P+T → FEC+T) in HER2-positive operable breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-02.
Abstract P1-14-12: Validation of residual cancer burden index (RCB) as a prognostic tool in patients with early breast cancer (EBC) treated with neoadjuvant chemotherapy (NAC): Comparison of RCB and Miller & Payne system (M&P)
Authors: Pons V , BurguÉs O , PÉrez-Fidalgo JA , MartÍnez MT , Pinilla K , Bermejo B , Lluch A
Published: May 2016

Pathological evaluation of response after NAC is a controversial issue. M&P has been for years the most widely employed score. Recently RCB index, a new system including axillary evaluation, seems to improve prognostic discrimination.

PURPOSE: The aim of this study was to validate the RCB index as a method to define prognosis in a reallife cohort of EBC patients treated with NAC and compare it to M&P system.

METHODS: We performed a retrospective analysis of our database. Patients with stage I-III considered candidate for NAC between January 2003 and August 2011 were included. RCB and M&P were calculated as previously published. Hormone receptor expression (RH), and Her2 were assessed following international guidelines. The Harell c-index and Roc curves were used to compare the prognostic value of RCB and M&P. Clinical, therapeutic and pathological data were obtained from medical records. A correlation with disease-free survival (DFS) and overall survival (OS) was done using the Kaplan-Meier method and Cox regression model.

RESULTS: 333 patients were included in this study. Distribution of breast cancer subtypes was: luminal 50.9%, Her2+ 31% and triple negative 18.1%. Mean tumour size was 42.3 mm. The majority of the patients had histhological grade II-III tumours (87.3%), with N stage 0-1 (97.3%). 87.4% received anthracycline and taxane-based NAC, associated to trastuzumab in her 2+ patients. Pathological complete response was 14% for the global population, being 30% for TN and 21.3% Her2+ subtypes. With a median follow-up of 56.3 months, DFS and OS at 5 years were as follows: RCB-0 93.6% and 97.9%, RCB-I 84.2% and 98.2%, RCB-II 79.1% and 89.5%, RCB-III 38.3% and 63.6%. Harell c-index value of RCB was statistically superior to M&P in both DFS (0.80 vs 0.68, p= 0.001) and OS (0.87 vs 0.69, p<0.001 ). This superiority value of RCB was consistent among all breast cancer subtypes.

CONCLUSION: RCB index is as more accurated prognostic score to predict DFS and OS compared to M&P.

Citation Format: Pons V, BurguÉs O, PÉrez-Fidalgo JA, MartÍnez MT, Pinilla K, Bermejo B, Lluch A. Validation of residual cancer burden index (RCB) as a prognostic tool in patients with early breast cancer (EBC) treated with neoadjuvant chemotherapy (NAC): Comparison of RCB and Miller & Payne system (M&P). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-12.
Abstract P1-14-18: Postmastectomy radiotherapy improves the outcomes of stage III breast cancer patients with negative lymph nodes after neoadjuvant chemotherapy
Authors: He M , Li J , Ni X-J , Chen S , Jiang Y-Z , Di G-H , Shao Z-M
Published: May 2016

Purpose: The aim of this study is to evaluate the role of postmastectomy radiotherapy (PMRT) in clinical stage II and III breast cancer patients who achieved negative node status (pN0) after neoadjuvant chemotherapy (NAC).

Material and methods: We retrospectively analyzed the outcomes of 143 patients with pN0 after NAC and mastectomy at Fudan University Shanghai Cancer Center. In total, 103 (72%) patients received PMRT, and 40 (28%) patients did not. Univariate and multivariate survival analyses were performed to evaluate the effect of PMRT on locoregional recurrence-free survival (LRRFS) and overall survival (OS) of the two groups.

Results: There were no differences between the two groups with respect to age, nuclear grade, estrogen receptor (ER) status, HER2/neu receptor status, lymphovascular space invasion (LVSI) status or pathological tumor size. However, a significantly higher proportion of patients in the irradiated group (64%) had clinical lymph node involvement than in the nonirradiated group (45%). After a median follow-up time of 49 months, 10 locoregional recurrence events occurred. For the entire cohort of patients, use of radiation therapy improved the 5-year LRRFS rate (94.5% vs. 80.2%; P =0.032) but not the 5-year OS rate (92.2% vs. 88.7%; P =0.617). In the subset of patients who presented with clinically stage II disease, the 5-year LRRFS and 5-year OS did not differ significantly between the PMRT and no-PMRT group (96.3% vs. 91.3%; P = 0.190 and 96.2% vs. 91.3%; P = 0.199, respectively). For patients with stage III disease at diagnosis, a trend was seen toward better local regional control with PMRT (the 5-year LRRFS rate was 92.7% vs. 64.2%; P = 0.063), although the benefit from radiation with respect to OS was not significant (5-year OS rate was 88.1% vs. 85.2%; P = 0.657). On multivariate Cox regression analyses, the clinical tumor size (hazard ratio [HR], 3.27; 95% confidence interval [CI], 1.05-10.18; P = 0.041), pathologic breast tumor response (HR, 1.82; 95% CI, 1,11-3.77; P = 0.046) and delivery of radiation therapy (HR, 1.27; 95% CI, 1.08-9.25; P = 0.047) were independent predictors of locoregional recurrence.

Conclusions: For patients who achieved pN0 after NAC, PMRT seemed to provide a clinical benefit for breast cancer patients with stage III disease. Omission of PMRT in patients with stage II disease did not increase the risk of locoregional recurrence and death.

Citation Format: He M, Li J, Ni X-J, Chen S, Jiang Y-Z, Di G-H, Shao Z-M. Postmastectomy radiotherapy improves the outcomes of stage III breast cancer patients with negative lymph nodes after neoadjuvant chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-18.
Abstract P1-15-04: Irriversible chemotherapy-induced alopecia in breast cancer patient
Authors: Kim S , Park HS , Kim JY , Nam S , Kim GM , Sohn JH , Kim SI
Published: May 2016

Introduction

Patients with breast cancer who received chemotherapy have distressing side effects such as mucositis, alopecia, gastritis, and BM suppression. Chemotherapy-induced alopecia(CIA) is one of considerable psychological events in self-esteem in patients with breast cancer, but the possibility of irreversible alopecia is often overlooked by physician.

We investigated clinical characteristics of CIA and prevalence of irreversible severe hair loss in patient with breast cancer who received chemotherapy.

Methods

We conducted a survey to collect demographic information about CIA with 150 breast cancer patients who had passed at least 6 months since their last day of chemotherapy from February 2015 to May 2015 in Yonsei Cancer Center. We obtained clinical information as age, elapsed time from end of chemotherapy, chemotherapy regimen, and other adjuvant therapy using their electrical medical records. We compared irreversible CIA characters between anthracycline and cyclophosphamide (AC) and taxane based regimen groups. The severe alopecia was defined as the hair density loss over 50% compared to the hair density before chemotherapy.

Results

The mean age at chemotherapy was 48 years old (±17.3) and the mean elapsed time after chemotherapy was 37 months (±9.5) in total patients.

Remnant alopecia was reported in 71 patients (47.3%). Wig or hat were used in 39 patients (26.0%).

The mean satisfaction score with a five-point scale was 4 in patients without alopecia or hair character change and 2.2 in patients with irreversible alopecia (p<0.001). The severe irreversible hair loss was complained by the 12 (8.2%) patients.

AC and taxane based chemotherapy were carried out in 65 and 85 patients, respectively. In AC group, remnant alopecia was shown in 18 patients (27.7%), and more than a half of patients in taxane group, 53 patients (62.4%), showed remnant alopecia (p<0.001). While only five patients (7.8%) in AC group suffered for severe hair loss, 26 patients (31.3%) in taxane group were affected by severe hair loss (p=0.001). The mean satisfaction level of hair status in patients in taxane group was 2.5 as compared to 3.6 in those in AC group (p<0.001).

Conclusion

Contrary to general expectation, About a half of breast cancer patients who received chemotherapy complained of irreversible hair loss even though at least 6 months has elapsed since the end of chemotherpy. In particular, patients with taxane based chemotherapy had more irreversible and severe alopecia than those with AC chemotherapy.

Citation Format: Kim S, Park HS, Kim JY, Nam S, Kim GM, Sohn JH, Kim SI. Irriversible chemotherapy-induced alopecia in breast cancer patient. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-15-04.