bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-10-16: In vitro delivery of model fluorescent dyes through the mammary papilla
Authors: Kurtz SL , Lawson LB
Published: February 2018

In the United States, 100,000 women each year are diagnosed with atypical hyperplasia (AH), significantly increasing their risk of developing breast cancer. However, only 40% of patients accept breast cancer preventive treatment, in part, due to systemic side effects. The localization of pre-cancerous cells within the ducts or lobules of the breast permits a local treatment strategy employing the innate mammary ducts. This expansive tree-like structure extends throughout the entire breast and may serve as a conduit for local delivery of therapeutics, thereby minimizing side effects associated with current preventive treatment strategies. This study examines how lipophilicity influences diffusion through porcine tissue using a model hydrophilic dye, Sulforhodamine B (SRB), and a model lipophilic dye, Nile Red (NR). Porcine nipple or skin tissue was positioned in a Franz diffusion cell and the formulations were applied topically. With equivalent dye concentrations applied to the donor surface, we noted no significant difference in total dye permeation when comparing diffusion through skin versus nipple tissue or when comparing SRB versus NR after 48 hours. However, the diffusion coefficient for both NR and SRB through the nipple was almost 700-fold greater compared to through the skin indicating improved drug delivery via the nipple. Additionally, after 48 hours there was significantly higher retention of SRB in the nipple and skin compared to NR. When we further looked at the distribution of each dye within the nipple using fluorescence microscopy, we saw a distinction in the localization of each dye. Fluorescence micrographs show that lipophilic NR is retained within the ducts while the hydrophilic SRB diffuses throughout the entire tissue section, suggesting that hydrophobicity impacts the ability of molecules to diffuse from the duct into the surrounding tissue. This suggests that lipophilic carriers may be effective for delivery of cancer therapeutics or preventative agents targeting the mammary ducts, where AH is localized.

Citation Format: Kurtz SL, Lawson LB. In vitro delivery of model fluorescent dyes through the mammary papilla [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-16.
Abstract P1-12-01: Withdrawn
Authors: Bardia A , Vahdat LT , Diamond JR , Kalinsky K , O'Shaughnessy J , Moroose RL , Isakoff SJ , Tolaney SM , Santin AD , Abramson V , Shah NC , Govindan SV , Maliakal P , Sharkey RM , Wegener WA , Goldenberg DM , Mayer IA
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P1-16-01: Tumor subtype concordance between breast and bone biopsies in bone only metastasis patients
Authors: Parkes AM , Clifton KK , Al Awadhi A , Oke OC , Warneke CL , Litton JK , Hortobagyi GN
Published: February 2018

Background:

Bone is the most common site of metastasis in metastatic breast cancer patients. Notably, bone biopsy is considered technically challenging with concerns regarding yield and reproducibility of immunohistochemistry technique. Our goal was to assess tumor subtype concordance between breast and bone biopsies done in patients with bone only metastases.

Methods:

We identified patients followed at MD Anderson Cancer Center for at least 6 months from 01/01/1997 to 12/31/2015 with bone as first site of metastasis. Breast and bone biopsy immunohistochemistry was used to categorize tumor subtype with hormone receptor positive (HR+) defined as ER or PR >1%. The following four tumor subtypes were identified: luminal A-like (HR+, HER2-), luminal B-like (HR+, HER2+), triple negative (HR-, HER2-), and HER positive (HR-, HER2+).

Results:

We identified 805 bone only metastasis patients with positive bone biopsies, 395 (49%) of which had hormone receptor and HER2 characterization available. Of these 395 patients, 293 (74%) were luminal A-like, 44 (11%) were luminal B-like, 51 (13%) were triple negative, and 7 (2%) were HER2 positive. Of these patients, we identified 281 patients with tumor subtype data available for both primary breast biopsy and bone metastasis biopsy, of which 237 (84%) were concordant, while 44 (16%) were discordant (Table 1).

Table 1. Concordance between breast and bone biopsies based on initial breast biopsy tumor subtypeBreast Biopsy Tumor Subtype (n = 281)Concordance with Bone Biopsy Tumor SubtypeDiscordant Bone Biopsy Tumor SubtypeLuminal A-like, HR+ HER2- (225/80%)Concordant: 199 (88%), Discordant: 26 (12%)10 Luminal B-like, 16 Triple negativeLuminal B-like, HR+ HER2+ (33/12%)Concordant: 19 (58%), Discordant: 14 (42%)11 Luminal A-like, 2 Triple negative, 1 HER2 positiveTriple negative, HR- HER2- (20/7%)Concordant: 16 (80%), Discordant: 4 (20%)3 Luminal A-like, 1 Luminal B-likeHER2 positive, HR- HER2+ (3/1%)Concordant: 3 (100%), Discordant: 0 (0%)NA

Conclusions:

When available, bone biopsy tumor subtype had significant concordance with breast biopsy tumor subtype in this large study of bone only metastasis patients. Discordant tumor subtype results were more common in patients with luminal B-like tumor subtype on initial breast biopsy.

Citation Format: Parkes AM, Clifton KK, Al Awadhi A, Oke OC, Warneke CL, Litton JK, Hortobagyi GN. Tumor subtype concordance between breast and bone biopsies in bone only metastasis patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-16-01.
Abstract P1-17-08: Efficacy of lapatinib and capecitabine combination therapy in brain metastases from HER-2 positive metastatic breast cancer: A systematic review and meta- analysis
Authors: Thein KZ , Zaw MH , Yendala R , Igid HP , Chai-Adisaksopha C , Hardwicke F , Awasthi S , Radhi S
Published: February 2018

Background:

Brain metastases contribute to significant morbidity and mortality in breast cancer. Approximately one fourth of breast tumors overexpress the human epidermal growth factor receptor 2 (HER2) protein and are twice as likely to develop brain metastases. There are currently no systemic therapies approved. We undertook a systematic review and pooled analysis of trials to determine the efficacy of lapatinib and capecitabine combination therapy in brain metastases from HER-2 positive metastatic breast cancer (MBC).

Methods:

We performed a comprehensive literature search using MEDLINE, EMBASE databases, and meeting abstracts through December 31, 2016. Trials that utilized lapatinib and capecitabine combination therapy in brain metastases from HER-2 positive MBC were incorporated in the analysis. The pooled estimated rates were calculated using random effects model. Heterogeneity was assessed using I2 statistic.

Results:

A total of 513 patients with brain metastases from HER-2 positive MBC from 6 trials and a subgroup of another 4 trials were included in our analysis. Lapatinib and capecitabine therapy was used as second-line treatment in 9 studies (n= 468) and as first-line treatment in the LANDSCAPE study (n= 45). Three studies were retrospective evaluations of randomized trials and the rest were phase 2 trials. CNS objective response rate (ORR) was 26% (95% CI: 19 – 33, I2: 65.9%). Complete response (CR) rate was 1% (95% CI: 0 - 2, I2: 0.0%) and partial response (PR) rate was noted at 24% (95% CI: 17- 31, I2: 66.1%). Stable disease (SD) occurred in 37% (95% CI: 29- 45, I2: 66.6%) and progressive disease (PD) in 19% (95% CI: 12- 25, I2: 66.5%). The first line LANDSCAPE study had the highest PR (49%) and ORR (53%) without a significant impact on CR rate; PD was 7%.

Conclusion:

Brain metastases in breast cancer is an area of urgent unmet need. Our meta-analysis showed that lapatinib/capecitabine therapy had some first line or second line activity in brain metastases from HER-2 positive MBC. Nevertheless, further randomized controlled trials are required in this patient population.

Citation Format: Thein KZ, Zaw MH, Yendala R, Igid HP, Chai-Adisaksopha C, Hardwicke F, Awasthi S, Radhi S. Efficacy of lapatinib and capecitabine combination therapy in brain metastases from HER-2 positive metastatic breast cancer: A systematic review and meta- analysis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-17-08.
Abstract P2-01-07: Isolation of viable CTCs from leukapharesis product with parsortix system enables subsequent culture
Authors: Neubauer H , Franken A , Driemel C , Lampignano R , Behrens B , Reinhardt F , Niederacher D , Stoecklein NH , Fischer JC , Fehm T
Published: February 2018

Background: Solid tumors are constantly releasing circulating tumor cells (CTCs) into the circulatory system. They are genotypically and phenotypically different from the primary tumor. Especially viable CTCs can be of high interest to obtain further therapeutically relevant information. Their extremely low frequency is one of the main limiting factors to use them for further characterization.

To overcome this challenge we tested to isolate viable CTCs from diagnostic leukapharesis (DLA) products obtained from breast cancer patients.

Material/methods: 16 DLA samples and matched peripheral blood (PB) samples of metastasized breast cancer patients were collected and CTC numbers were determined by CellSearch® analysis. Viable cells were enriched from DLA product with Parsortix system. Genomic DNA of single cultured CTCs was isolated and amplified by whole genome amplification. Array-based comparative genomic hybridization of single cells was performed to analyze for genomic aberrations. Resulting profiles were compared to genomic aberration profiles of CTCs isolated before in vitro culture.

Results: CTCs were detected in ten PB and matched DLA samples and in three more DLA samples whose corresponding blood samples were CTC-negative. CTC number per ml was increased by an average of 22.5 fold. Parsortix was optimized to enrich tumor cells from DLA product while keeping them best viable. An enrichment rate of 67.7% ± 11.3% and a harvesting rate of 65.3% ± 9.7% were determined with spiked MCF7 cells. We could grow viable CTCs from three out of eight CTC positive DLA samples from metastasized patients as determined by immune fluorescence analysis. The growing cells harbor genomic anomalies confirming their malignant origin. Most aberrations are widely identical to the aberrations detected in uncultured CTCs.

Conclusions: DLA provides greater numbers of viable CTCs which can be enriched with Parsortix system in order to enable their in vitro cultivation. This workflow will allow functional studies.

Citation Format: Neubauer H, Franken A, Driemel C, Lampignano R, Behrens B, Reinhardt F, Niederacher D, Stoecklein NH, Fischer JC, Fehm T. Isolation of viable CTCs from leukapharesis product with parsortix system enables subsequent culture [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-01-07.
Abstract P2-02-13: Utilization of cell-free circulating tumor DNA for management of breast cancer: Practices in academic and community oncology
Authors: Thomas RA , Klar N , Kiedrowski L , Nagy RJ , Lee AV , Brufsky A
Published: February 2018

Background: Next-generation sequencing (NGS) of cell-free DNA (cfDNA) is increasingly being utilized to assess somatic genomic alterations in patients with breast cancer. We investigated the clinical use of such testing in breast cancer care in a major healthcare system with both academic and community-based practices. We also explored the observed genomic landscape in the analyzed patient cohort and whether treatment plans were modified based on the results.

Methods: A retrospective review of cfDNA NGS results (Guardant360) ordered at the University of Pittsburgh Medical Center for patients with breast cancer from 7/2015-3/2017 was performed. Test ordering patterns, the landscape of genomic alterations identified, and clinical use of select results were assessed.

Results: During this period 95 samples were submitted, 73 (77%) ordered by academic center providers and 22 (25%) from community providers. Alterations were detected in 88 samples (93%) with a median of 3 alterations per test. Five patients had serial samples ordered assessing dynamic cfDNA across clinical treatment and progressions, leaving 84 unique patients in the dataset. The average patient age was 57, and 95% of patients were female. Patients were most often observed to have alterations in TP53 (51%), PIK3CA (44%), and ESR1 (26%). Additional clinical data were collected for 48 patients with mutations or amplifications in PIK3CA, ESR1, and/or ERBB2 (HER2) to assess for clinical use of genomic information. Results were used to change clinical care in 13 (27%) of these cases. Community providers were more likely to use genomic results to guide clinical management in these cases (9/16, 56%) than academic providers (4/32, 12.5%), p=0.001. Of this patient subset, those with tests ordered by an academic provider had more lines of prior therapy at the time of testing vs. those in the community (average 5.9 vs 3.4 respectively, p=0.019).

Conclusions: CfDNA NGS analysis for somatic genomic alterations in breast cancer is being ordered clinically by both academic and community practices within this healthcare system. Results for a subset of clinically annotated patients were acted on more frequently by community-based ordering providers, which may be related to patients tested at academic sites having had more lines of prior treatment.

Citation Format: Thomas RA, Klar N, Kiedrowski L, Nagy RJ, Lee AV, Brufsky A. Utilization of cell-free circulating tumor DNA for management of breast cancer: Practices in academic and community oncology [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-02-13.
Abstract P2-04-07: Triple negative breast cancer-specific chromatin conformation links Notch signal to tumor-specific transcriptional program
Authors: Petrovic J , Zhou Y , Georgakilas G , Vahedi G , Pear WS , Faryabi RB
Published: February 2018

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is currently incurable with conventional chemotherapy. Some TNBC patients harbor either recurrent somatic gain-of-function mutations or focal amplification in genes coding for Notch receptors. Recent findings suggest that Notch signals, in the absence of Notch mutations are also important to maintain chemotherapy-resistant circulating tumor cells. Importantly, elevated Notch signaling is specifically enriched in the TNBC and is associated with worse survival in this subtype. These findings underscore the importance of Notch signaling in pathogenesis of TNBC and suggest potential new avenue for therapeutic approaches. Despite this, the target genes and oncogenic mechanisms downstream of aberrant Notch signaling are poorly understood. To create a high confidence map of the oncogenic Notch-driven regulome in TNBC, we performed an integrative, comprehensive and functional genome-wide analysis of Notch-driven targets in Notch-mutated TNBC cell lines by combining high-resolution genome-wide chromatin topology data (HiChIP), dynamic mapping of Notch transcriptional complex members and active and repressive chromatin marks (ChIP-seq), as well as evaluation of dynamic transcription (RNAseq) in presence and absence of Notch signals. One important oncogene and critical Notch target in TNBC is MYC. Our integrative analysis identified detailed map of Notch-dependent MYC regulatory network. The TNBC-specific MYC regulatory region, located 5' of MYC, is much more complex compared to other known Notch-driven malignancies and constitutes of a broad domain of active enhancers marked by H3K27ac that are not present in Notch-driven lymphoma and leukemia. Integrative analysis of ChIP-seq and HiChIP revealed multiple enhancers within this broad domain of regulatory elements that are directly bound by the members of Notch transcriptional complex, sensitive to acute changes in Notch activation and that contact MYC promoter via tumor specific chromatin loops. We showed that genetic perturbation of MYC by CRISPR/Cas9 approach was sufficient to kill TNBC cells. Since, MYC is difficult to target pharmacologically an alternative strategy is to use drugs that inhibit factors regulating MYC expression. To this end, elucidating the Notch regulatory landscape, and in particular, the mechanism by which Notch regulates MYC expression in TNBC may reveal new therapeutic strategies to precisely target MYC in Notch-dependent breast cancer.

Citation Format: Petrovic J, Zhou Y, Georgakilas G, Vahedi G, Pear WS, Faryabi RB. Triple negative breast cancer-specific chromatin conformation links Notch signal to tumor-specific transcriptional program [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-04-07.
Abstract P2-05-05: Not presented
Authors: Fortunato A , King L , Mallo D , Hall A , Aktipis A , Marks JR , Hwang S , Maley CC
Published: February 2018

This abstract was not presented at the symposium.
Abstract P2-05-09: Withdrawn
Authors: Popova T , Manie E , Stern M-H
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P2-05-11: Not presented
Authors: Ngo C , Borcoman E , Simaga F , Mariani O , Fuhrmann L , Jeannot E , Loirat D , Lae M , Pierga J-Y , Pierron G , Vincent-Salomon A
Published: February 2018

This abstract was not presented at the symposium.
Abstract P2-11-03: Not presented
Authors: Jimenez RB , Yeap B , Hickey S , DePauw N , Batin E , Taghian AG , Lu H-M , MacDonald SM
Published: February 2018

This abstract was not presented at the symposium.
Abstract P2-11-05: Not presented
Authors: Cernusco NLV , Marciai N , de Liguoro M , Giri MG , Guariglia S , Lombardi D , Pellini F , Cavedon C , Pollini GP , Mazzarotto R
Published: February 2018

This abstract was not presented at the symposium.
Abstract P2-11-13: Meta-analysis of local recurrence of invasive breast cancer after electron intraoperative radiotherapy
Authors: Harness J , Shah C , Brooks E , Via C , Vicini F
Published: February 2018

Background: Electron intraoperative radiotherapy (IORT) can be used during breast conservation surgery to treat early-stage invasive breast cancer. While IORT may be an attractive alternative to traditional post-operative radiotherapy for many patients, its effectiveness in preventing local recurrence is still being evaluated. Using data from current clinical and observational studies, we aimed to assess the impact of single-fraction electron IORT on local recurrence rates.

Methods: Studies on single-fraction electron IORT during breast conservation surgery were identified through a search of PubMed and Google Scholar, as well as secondary referencing. Local recurrence rate was the main outcome of interest. Protocols from each publication were assessed for potential sources of heterogeneity. A meta-analysis of proportions, using binomial distribution to model the within-study variability and a random effects model, was conducted to estimate a pooled local recurrence rate. In order to estimate a 5-year recurrence rate, we applied a single-sample Poisson-normal model to model the probability of events occurring during a fixed period of time (60 months).

Results: A total of 13 independent publications were identified for abstraction. The analysis demonstrated a pooled monthly local recurrence rate of 0.02% per person-month (95% CI: 0.00 – 0.06%) for the studies with < 5 years of follow-up, 0.03% per person-month (0.02 – 0.06%) for studies with ≥ 5 years of follow-up, and 0.02% per person-month (0.01 – 0.04%) overall. Based on this model, the predicted 5-year recurrence rate is 2.7%, with a 95% confidence interval of 1.9% - 3.7%.

Conclusions: According to the published literature, the rate of breast cancer local recurrence after electron IORT was 0.02% per person-month; with an adjusted 5-year recurrence rate of 2.7%. These findings support the recent guidelines from the American Society for Radiation Oncology (ASTRO) supporting the use of electron IORT in low-risk patients.

Citation Format: Harness J, Shah C, Brooks E, Via C, Vicini F. Meta-analysis of local recurrence of invasive breast cancer after electron intraoperative radiotherapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-13.
Abstract P2-11-21: A prospective phase II study of TARGeted Intraoperative radioTherapy boost plus whole breast irradiation in breast cancer patients undergoing breast-conserving treatment
Authors: Lee HW , Yoon C , Ahn SG , Kim JW , Cha YJ , Lee IJ , Jeong J
Published: February 2018

Background: TARGIT-A trial showed that intraoperative radiotherapy (IORT) using Intrabeam® concurrent with lumpectomy within a risk-adapted approach could be considered as an option for eligible patients with early breast cancer. To introduce IORT in clinical practice for Korean breast cancer patients, safety profiles for this new technique from clinical trial with Korean are required due to ethnic (anatomical) difference. Acute toxicity is a key hurdle for patients receiving IORT, because IORT may affect wound healing and increase wound complications. We conducted a phase II study as a feasibility test of IORT at the dose of 20 Gy for the replacement of boost-EBRT in Korean women who are candidates for breast-conserving treatment.

Methods: This single-arm trial aimed to investigate acute toxicity occurred within 6 months after IORT. In 1,119 patients receiving EBRT from TARGIT-A trial, the incidence of acute toxicity within 6 months is 15%. Compared with WBRT, we aim to prove a non-inferiority of IORT with 20 Gy. A sample size of 195 achieves 80% power to detect a non-inferiority proportion (P0) of 0.2300 using a one-sided binomial test for non-inferiority. These results assume that the actual proportion (P1) is 0.1500. Considering a drop-out rate of 10%, the trial would need to enroll 215 patients in total. This trial is registered with ClinicalTrials.gov, number NCT02213991.

Results: From August 2014 to November 2016, 233 women with early breast cancer were screened, and 215 undergoing IORT were enrolled. In 36 women, clinically significant complications during acute period are noted. The rate of patients experiencing acute toxicity was 16.7% (95% CI, 11.8-21.7%). The actual non-inferiority margin of our trial was 21.7% under the pre-specified margin as 23.0%. In details, There are 31 with seroma collection (more than 3 times when aspiration volume is over 10cc), 2 with wound infection, and 5 with skin break down. At a median follow-up of 17.8 months, there is no local recurrence.

Conclusions: Targeted intraoperative radiotherapy using Intrabeam® is a safe procedure for Korean breast cancer patients with acceptable toxicity profile in acute period.

Citation Format: Lee HW, Yoon C, Ahn SG, Kim JW, Cha YJ, Lee IJ, Jeong J. A prospective phase II study of TARGeted Intraoperative radioTherapy boost plus whole breast irradiation in breast cancer patients undergoing breast-conserving treatment [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-21.
Abstract P2-12-06: Re-excision rates in breast conserving surgery for invasive breast cancer after neoadjuvant chemotherapy with and without the use of a radiopaque tissue transfer and X-ray system
Authors: Kolberg H-C , Akpolat-Basci L , Stephanou M , Wetzig S , Cubuk Y , Gerharz J , Liedtke C
Published: February 2018

Background: Published re-excision rates after breast conserving surgery for invasive breast cancer vary between 20 and 50%. In patients after neoadjuvant chemotherapy even higher re-excision rates may result from difficulties in defining the surgical target particularly in cases with excellent treatment response. Specimen radiography is reducing re-excision rates, however, defining involved margins is often difficult using standard approaches. Devices allowing horizontal and vertical examination and an exact topographic localization of the lesion in the resected tissue could reduce re-excision rates by an intraoperative detection of involved margins.

Methods: 80 patients with invasive breast cancer receiving breast conserving surgery after neoadjuvant chemotherapy and an indication for wire marking by mammography were included in this analysis. All tumors were marked with titanium clips prior to chemotherapy. In 40 patients specimen radiography was performed in a standard approach (control group), in 40 patients a tissue transfer and X-ray system based on a non-radiopaque board with radiopaque topographic markers and a stand for cranio-caudal X-rays was used (study group). A univariate analysis was carried out to evaluate the association between the use of the radiopaque tissue transfer system and the re-excision rate using a logistic regression model. Calculations were performed using the XLSTAT Biomed Software (Version 19.03, Addinsoft, NY, USA.).

Results: 19/80 patients (23.75%) required re-excision because of involved margins; among those patients, 14/40 (35%) were in the control group and 5/40 (12.5%) in the study group. The association between the use of the radiopaque tissue transfer system and the lower re-excision rate was statistically significant (p=0.023).

Conclusion: Our analysis provides a rationale for the use of a radiopaque tissue transfer system for specimen radiography in breast conserving surgery after neoadjuvant chemotherapy for invasive breast cancer in order to reduce re-excision rates. Based on these results we are planning a study including also patients receiving primary surgery.

Citation Format: Kolberg H-C, Akpolat-Basci L, Stephanou M, Wetzig S, Cubuk Y, Gerharz J, Liedtke C. Re-excision rates in breast conserving surgery for invasive breast cancer after neoadjuvant chemotherapy with and without the use of a radiopaque tissue transfer and X-ray system [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-12-06.
Abstract P3-01-09: Re-evaluating the “10% rule” for sentinel lymph node biopsy with radioactive method in breast cancer; a single institutional retrospective study
Authors: Miyamoto H , Aruga T , Onishi M , Goto R , Iwamoto N , Idera N , Horiguchi K , Honda Y
Published: February 2018

Background:

When multiple radioactive sentinel lymph nodes (SLNs) are present during sentinel lymph node biopsy (SLNB), excision of those SLNs with >10% radioactive count per minute (high-CPM) of the most radioactive node (“10% rule”) has been proposed. Although this “10% rule” may avoid excessive removal of SLNs,the risk of false negative and remnant positive SLNs in the patients who have SLNs with <10% CPM (low-CPM) remain unclear. The purpose of this analysis is to determine the clinical validity of this “10% rule” for early breast cancer patients.

Method:

We reviewed the records of successful SLNBs using the radioisotope (RI) method performed between January 2001 and December 2016 in our institution. The radioactive count from each excised SLN was measured. Non-radioactive lymph nodes were excluded from this analysis. All SLNs were pathologically assessed by 2mm serial section with hematoxylin and eosin staining.

Results:

In the 3,043 patients with successful SLNB,the median number of radioactive SLNs removed was 2 (mean, 1.8; range, 1-10) and 599 patients (19.7%) had SLNs with low-CPM. The total number of radioactive SLNs was 5,472, and 875 (16.0%) out of 5,472 SLNs were low-CPM. Sixty-one (7.0%) out of these 875 SLNs with low CPM in 56 patients (1.8%) had metastatic disease by pathological assessment. The number of metastatic SLN with low-CPM was one in 51 patients and two in 5 patients. Nineteen patients (0.6%) had no metastatic lesion in SLNs with high-CPM.

Discussion and Conclusions:

If SLNB was performed by RI method alone with “10% rule”, false negative rate increased by 0.6% and underestimation increased up to 1.8%. Furthermore, 19.7% of the patients have the benefit of avoiding excessive removal of SLNs.Considering the risk and benefit, “10% rule” is a high validitymethod to capture metastatic SLNs even in the setting that ALND will not be performed.

Citation Format: Miyamoto H, Aruga T, Onishi M, Goto R, Iwamoto N, Idera N, Horiguchi K, Honda Y. Re-evaluating the “10% rule” for sentinel lymph node biopsy with radioactive method in breast cancer; a single institutional retrospective study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-01-09.
Abstract P3-01-12: Withdrawn
Authors: You JY , Bae SY , Jung SP , Lee ES
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P3-01-14: Nomogram predicting axillary lymph node metastases to skip intraoperative analysis of sentinel lymph nodes
Authors: Park JH , Ju YW , Kim KE , Rhu J , Kim Y , Lee E , Lee H-B , Moon H-G , Noh D-Y , Han W
Published: February 2018

Background: According to the American College of Surgeons Oncology Group Z0011 trial, complete axillary lymph node dissection (ALND) did not affect survival of patients with clinical T1-T2 invasive breast cancer and one to two sentinel lymph nodes (SLNs) metastases treated with lumpectomy, adjuvant systemic therapy, and radiation therapy. A significant proportion of breast cancer patients may not require ALND, in whom intraoperative analysis of SLNs can be omitted reducing operation time and cost. The aim of this study was to develop a nomogram predicting three or more axillary lymph nodes (ALNs) metastases based on preoperative imaging and clinicopathological factors.

Methods: The training set consisted of 1030 patients with clinical T1-T2 invasive breast cancer and clinically negative ALN who received surgery at Seoul National University Hospital (SNUH) between January 2010 and December 2013. Preoperative imaging techniques including ultrasonography (US), computed tomography (CT), positron emission tomography (PET), and clinicopathological features associated with three or more ALN metastases were evaluated by logistic regression analysis. A nomogram predicting three or more ALNs was developed with statistically significant factors. The validation set consisted of 781 independent patients who received surgery at SNUH between January 2014 and December 2015.

Results: Of the 1030 patients, 89 (8.6%) had three or more ALN metastases. Multivariate analysis showed that three or more ALN metastases was independently associated with tumor size (cm) by US (p<0.001), suspicious ALNs findings in US (p<0.001), chest CT (p<0.001), and PET/CT (≥ 1.4 SUV, p<0.001). Established nomogram evaluating the probability of three or more ALNs metastases includes the above four associated factors. The areas under the receiver operating characteristic (ROC) curve of the nomogram were 0.866 (95% confidence interval [CI] 0.826-0.905) for the training set and 0.867 (95% CI: 0.801-0.932) for the validation set. With cutoff point of 142, false negative ratio is 3.6%, and 8.6% of patients were candidates for intraoperative SLN analysis.

Conclusion: Patients with a strong possibility of three or more ALNs metastases can be identified using preoperative imaging methods including US, CT, and PET. The nomogram measuring this prospect may be valuable in skipping intraoperative analysis of SLNs with advantage of reduced operation time and cost.

Citation Format: Park JH, Ju YW, Kim KE, Rhu J, Kim Y, Lee E, Lee H-B, Moon H-G, Noh D-Y, Han W. Nomogram predicting axillary lymph node metastases to skip intraoperative analysis of sentinel lymph nodes [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-01-14.
Abstract P3-01-17: Evaluation of “Systematic sonographic axillary staging” on clinically node positive breast cancer patients becoming clinically node negative after neoadjuvant chemotherapy
Authors: Ozmen T , Lazaro M , Vinyard A , Avisar E
Published: February 2018

Purpose

Accumulating evidence supports usage of sentinel lymph node biopsy (SLNB) for clinically node positive (cN+) breast cancer (BC) patients, who become clinically node negative (ycN-) after neoadjuvant chemotherapy (NAC). How to reassess the axilla after NAC is a challenging issue. In our institution, Systematic Sonographic Axillary Staging (SSAS) is currently being tested in this group of patients. The aim of this study is to analyze the early results of this approach.

Method

During initial presentation, systematic sonographic axillary staging is done preferentially by the surgeon. Needle biopsy is then performed of suspicious node(s). At completion of NAC, the axilla is again systematically staged sonographically, taking into account the pre-treatment disease locations. Any residual morphologically suspicious node undergoes a repeat needle biopsy. According to the evidence of residual disease, the patient is either scheduled for axillary dissection (AD) or for SLNB.

We analyzed early results of SSAS on patients, who converted ycN (-) after NAC. Strictly adherence to SSAS protocol was the only inclusion criteria.

Results

A total of 25 patients were included. On repeat axillary USG after NAC, 11 patients had normal appearing and 14 patients had suspicious appearing lymph nodes (LNs). 14 patients underwent repeat biopsy; 9 patients had benign and 5 patients had malign pathology results. 20 patients underwent SLNB. Among 20 patients, 12 patients had negative SLNB and 8 patients had positive SLNB (4 patients had benign appearing LNs on repeat USG and 4 patients had benign biopsy results). 13 patients underwent AD (8 patients after positive SLNB and 5 patients directly after positive US-guided biopsy result). Among 8 patients with positive SLNB, 4 patients had macrometastatic disease (>2mm) on SLNB. In 3 of these 8 patients, no additional disease was found on AD, while 1 patient had only isolated tumor cell and 1 patient had only micrometastasis (Table 1).

Table 1. Size of the axillary involvement among patients with positive SLNB Sentinel Lymph Node BiopsyAxillary DissectionPatient #LN* (+) / Total LNs removedSize of involvement (mm)LN* (+) / Total LNs removedSize of involvement (mm)11/611/50.122/42.50/5-31/363/19141/210/3-51/11.50/21-62/21.53/32.573/357/10384/447/133* LN = lymph node

Conclusion

Systematic sonographic axillary staging is a reliable approach to cN (+) patients, who become ycN0 after NAC. This observation should be tested in a larger study.

Citation Format: Ozmen T, Lazaro M, Vinyard A, Avisar E. Evaluation of “Systematic sonographic axillary staging” on clinically node positive breast cancer patients becoming clinically node negative after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-01-17.
Abstract P3-03-06: Telomerase polymorphism and breast cancer
Authors: Alvares MM , Rodrigues KS , Matos JN , Oliveira DM
Published: February 2018

Introduction:

Telomerase is an enzyme responsible for telomere maintenance in almost all human cancer cells, but generally not expressed in somatic ones. The minimum essential components of telomerase are the catalytic subunit, telomerase reverse transcriptase (TERT), and a non- coding RNA (TERC); TERT reverse transcribes telomere DNA using TERC as the template (1). Given the fundamental role of TERT in oncogenesis, polymorphisms of genes related to telomerase may influence the expression levels of this enzyme, influencing the host's susceptibility to tumor progression and metastasis [2,3]. Some studies have linked these polymorphisms with susceptibility and/or survival of patients with breast cancer [2,4,5,6]. In this work, we analyzed a region in the second intron of the gene TERT, located in chromosome 5p15.33, by sequencing, in order to find mutations associated with clinical aspects. The DNA of 65 patients with breast cancer were evaluated.

Methodology:

The population consisted of breast cancer patients who accepted to participate in the study, attended from March 2015 to September 2016 at a public hospital (HUB) and a private center for cancer treatment (Cettro®), both in Brasília city – Brazil. Standard DNA extraction from blood samples was performed by dehydration and precipitation with saturated NaCl solution. The concentration and purity of the DNA were determined by spectrophotometry using the NanoDrop One equipment® (Themo Scientific, Madison, USA). The region of interest was amplified by conventional PCR. The primer sequences were: F: 5'-ATG CGA CAG TTC GTG GCT CA-3 'and R: 5'-ATC CCC TGG CAC TGG ACG TA-3'. The sequencing was performed in the AB 3500 Genetic Analyzer® (Applied Biosystems). Data were analyzed by using software Chromas Lite ® (2.01, Technelysium Pty Ltd.) and the BLAST (NCBI - http://blast.ncbi.nlm.nih.gov/Blast.cgi). GraphPad Prism software version 7.02 was used for statistical analyzes.

Results and Conclusion:

A total of 65 patients were selected for DNA analysis. We identified a recurrent mutation (C>T) among them. The allelic frequencies were 0,79 for C and 0,21 for T. Only three patients had genotype TT, but 21 were heterozygous (CT). This polymorphism was significantly associated with tumor grade, the presence of T allele were implicated in more aggressive (grade 3) tumors (p=0.028, chi-square test). Those patients whith genotype CT were at greater risk them others whith CC genotype of having high grade (3) breast tumors (odds ratio = 6.13, 95% confidence interval 1.46, 25.74; relative risk 1.9, 95% confidence interval 1.02, 3.59).

Citation Format: Alvares MM, Rodrigues KS, Matos JN, Oliveira DM. Telomerase polymorphism and breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-03-06.
Abstract P3-04-06: Genomic analysis of cancers arising in breasts with different mammographic density
Authors: Gorringe KL , Hughes S , Nickson C , Devereux L , Pridmore V , Rowley SM , Byrne DJ , Cheasley D , Kavanagh AM , Mann GB , Fox SB , Campbell IG
Published: February 2018

Background: High mammographic density (MD) is a known risk factor for breast cancer, but it is currently unknown whether this altered microenvironment leads to the development of genomically different tumours.

Method: We used lifepool, an Australian prospective population-based cohort of over 53,000 women currently in a mammographic screening program, to identify >1000 cases of breast carcinoma (in situ and invasive breast cancer) for analysis. Pathology reports, detection modality (screen-detected/interval), MD data (AutoDensity, Nickson et al., 2013 DOI:10.1186/bcr3474), germline DNA and tumor tissue were available for a subset of cases. Tumours were classified into quintiles, depending on the relative MD ranking of the most recent normal mammogram. Tumour DNA was analysed using Affymetrix OncoScan MIP arrays or using a targeted Agilent SureSelect and Illumina sequencing panel of 105 genes relevant to breast cancer. Copy number and mutation data were compared between tumours from the highest (high-MD) and lowest (low-MD) quintiles of MD.

Results: Preliminary analysis found no significant differences in clinico-pathological features between tumours from breasts with high-MD (n=38) and low-MD (n=35). Genomic analysis of 8 high-MD tumours and 8 low-MD tumours identified chromosome 15 loss as being significantly enriched in low-MD tumours. Only Low-MD tumours to date contained TP53 mutation (3/8). Data will be presented from at least an additional 9 low-MD and 15 high-MD tumours currently undergoing genomic assays.

Conclusion: When complete, our data will be the first to evaluate the somatic genetic events in tumours arising in low-MD and high-MD breasts. Although our cohort to date is small, it may be possible that tumours from extremes of MD have different genomic characteristics.

Citation Format: Gorringe KL, Hughes S, Nickson C, Devereux L, Pridmore V, Rowley SM, Byrne DJ, Cheasley D, Kavanagh AM, Mann GB, Fox SB, Campbell IG. Genomic analysis of cancers arising in breasts with different mammographic density [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-04-06.
Abstract P3-04-08: Genomic analysis of breast papillomas
Authors: Elder KJ , Kader T , Hill P , Opeskin K , Goode DL , Pang J-M , Fox SB , Mann GB , Campbell IG , Gorringe KL
Published: February 2018

Background: Papillomas are often found co-existing with breast carcinoma yet they are not considered to be a true precursor of the disease. Previous studies have shown that some cases may carry copy number alterations (CNA) or mutations in AKT1/PIK3CA (Troxell et al., 2010, Modern Pathology 23: 27-37) suggesting this lesion may have malignant potential. To date, a detailed study of both pure papillomas (not associated with cancer) and those seen in the same breast as a carcinoma has not been undertaken. Therefore, we set out to investigate the molecular changes associated with this lesion and whether papillomas can be clonally related to synchronous breast carcinoma.

Method: Papilloma cases were identified from a hospital database and independently reviewed by consultant pathologists followed by micro-dissection of formalin-fixed paraffin-embedded tumour tissue and DNA extraction. For CNA detection either Affymetrix Molecular inversion Probe (MIP) 330K arrays were used or low-coverage whole genome sequencing using 5-10 ng of DNA (Kader et al., 2016, Genome Medicine 8: 121) where there was insufficient DNA for MIP arrays. We applied either of these 2 methods to 24 cases of pure papilloma as well as 20 papilloma with synchronous ductal carcinoma in situ (DCIS) and/or invasive ductal carcinoma (IDC). Additionally, targeted exon sequencing of breast cancer driver genes was performed for a subset of cases.

Results: Among the pure papillomas 31% (5/16) showed CN change with, the most frequent change being 16q loss (2/16). Of the papillomas synchronous with DCIS/IDC analysed to date, 2/5 were shown to be clonal with the co-existing carcinoma. Final CNA analysis will be presented for 24 pure papilloma cases and 20 synchronous cases.

Targeted sequencing revealed that all for pure papillomas analysed to date harboured somatic mutations in PIK3CA (3/4 cases) and PIK3R1 (1/4,) suggesting that most papillomas are driven by alterations in the PI3-kinase/AKT pathway. The final sequencing data to be presented will include an additional 5 pure papillomas and 10 synchronous cases.

Conclusion: Our observation that 40% of papillomas are clonal to breast carcinoma suggests that DCIS or IDC can arise from a common ancestor as co-existing papillomas, however, most papillomas co-existing with carcinoma are likely to be independent in our cohort.

Citation Format: Elder KJ, Kader T, Hill P, Opeskin K, Goode DL, Pang J-M, Fox SB, Mann GB, Campbell IG, Gorringe KL. Genomic analysis of breast papillomas [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-04-08.
Abstract P3-05-05: Class IIa HDAC inhibition promotes an anti-tumor macrophage phenotype that induces breast tumor regression and inhibits metastasis
Authors: Guerriero JL , Sotayo A , Ponichtera HE , Castrillon JA , Pourzia AL , Schad S , Johnson SF , Carrasco RD , Lazo S , Bronson RT , Davis SP , Lobera M , Nolan MA , Letai A
Published: February 2018

While tumor-associated macrophages (TAMs) often have net pro-tumor effects, their embedded location and their untapped potential provide impetus to the discovery of strategies to turn them against tumors. We recently reported that a first in class selective class IIa HDAC inhibitor (TMP195) influenced human monocyte responses to colony stimulating factors CSF-1 and CSF-2 in vitro. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumor microenvironment and reduces tumor burden and pulmonary metastases through macrophage modulation. TMP195 induces recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumors. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumor reduction. These data introduce class IIa HDAC inhibition as a novel means to harness the anti-tumor potential of macrophages to enhance cancer therapy.

Citation Format: Guerriero JL, Sotayo A, Ponichtera HE, Castrillon JA, Pourzia AL, Schad S, Johnson SF, Carrasco RD, Lazo S, Bronson RT, Davis SP, Lobera M, Nolan MA, Letai A. Class IIa HDAC inhibition promotes an anti-tumor macrophage phenotype that induces breast tumor regression and inhibits metastasis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-05-05.
Abstract P3-05-07: Improving CAR T cell function by reversing the immunosuppressive tumor environment of breast cancer
Authors: Bajgain P , Tawinwung S , Watanabe N , Sukumaran S , Anurathapan U , Heslop HE , Rooney CM , Brenner M , Leen AM , Vera JF
Published: February 2018

Adoptive transfer of T cells redirected to tumor-associated antigens (TAAs) by expression of chimeric antigen receptors (CARs) can produce tumor responses, even in patients with resistant malignancies. To target breast cancer, we generated T cells expressing a CAR directed to the TAA mucin-1 (MUC1). T cells expressing this CAR (86±1.9%, n=5) specifically killed MUC1-expressing cells (MDA-MB-468 – 45.9±7.3%, MCF-7 – 36.8±3.6) but not MUC1(-) 293T cells (3.7±1.6% specific lysis, 20:1 E:T, n=3). Although these CAR T cells had potent anti-tumor activity against breast cancer cells, when exposed to the Th2-polarizing cytokine IL4 [which is upregulated in tumor samples (Oncomine, p<0.05)] we observed a dramatic reduction in their cytolytic potential [IL2 - 45.9±7.3% vs IL4 - 11.3±3.7% specific lysis, 20:1 E:T ratio, n=4]. Thus, to protect our CAR.MUC1 T cells from the negative influences of IL4, we generated an inverted cytokine receptor (ICR) in which the IL4 receptor exodomain was fused to the IL7 receptor endodomain (4/7 ICR). Transgenic expression of this molecule in CAR.MUC1 T cells (55±4.8% double positive cells, n=5), restored the cytolytic function of CAR T cells (30.9±8.1% specific lysis, 20:1 E:T, n=3). Next, to determine the long term effects of this modification we co-cultured transgenic T cells with MUC1+ tumor cells and measured tumor and T cells numbers. In the presence of IL4, only double positive (CAR.MUC1-4/7) T cells expanded and eliminated the tumors in vitro and in vivo. However, upon tumor elimination, transgenic T cells rapidly contracted, demonstrating the antigen- and cytokine-dependence of the product. In conclusion, CAR.MUC1-4/7 T cells can effectively target breast cancer cells and retain their cytotoxic function even in the IL4-rich tumor microenvironment.

Citation Format: Bajgain P, Tawinwung S, Watanabe N, Sukumaran S, Anurathapan U, Heslop HE, Rooney CM, Brenner M, Leen AM, Vera JF. Improving CAR T cell function by reversing the immunosuppressive tumor environment of breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-05-07.