bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-10-17: Radiotherapy associated with concurrent bevacizumab in patients with non-metastatic breast cancer
Authors: Dautruche A , Belin L , Cottu P , Bontemps P , Lemanski C , De La Lande B , Baumann P , Missohou F , Levy C , Peignaux K , Reynaud-Bougnoux A , Denis F , Gobillion A , Ady Vago N , Fourquet A , Kirova Y
Published: March 2017

Purpose/Objectives

The purpose of this study was to determine early and late toxicities among patients with non-metastatic breast cancer (BC) receiving concurrent bevacizumab (BV) and radiation therapy (RT).

Materials/Methods

Multicentre, prospective study, of the toxicity of adjuvant concomitant association of BV and RT in patients with non-metastatic BC enrolled in Phase 3 BEATRICE, BEVERLY and BETH trial. Early and late toxicities were assessed by the Common Terminology Criteria for Adverse Events v. 3.0 during RT, 12 months and 36 months after its completion.

Results

Sixty-four patients were included from october 2007 to august 2010. They all received adjuvant RT and BV concomitant treatment, plus neo-adjuvant BV for 24 patients. RT was adjuvant and normo-fractionated. Twelve months toxicity was available for 60 patients and 36 months toxicity was available for 43 patients. Median follow-up was 46 months (18-77). Median age was 51 years old (23-68). Among 63 evaluated patients during RT, acute radiation dermatitis was observed in 48 (76%) patients : Grade 1 for 27 (43%), grade 2 for 17 (27%), grade 3 for 4 patients (6%). Grade 2 acute oesophagitis was observed in 1 patient. At 3 years, few toxicities were observed : 6 patients (14%) had grade 1 pain, 4 (9%) had grade 1 fibrosis, one (2%) had grade 1 telangiectasis, one (2%) had grade 1 paresis, 3 (7%) had grade 1 lymphoedema and one grade 3 lymphoedema. No grade 4 toxicity was observed. At 12 months, only one evaluated patient had a LVEF <50% and none at 36 months.

Conclusions

Concurrent bevacizumab with locoregional RT is associated with acceptable early and late 3-years toxicities in patients with BC. Determination of late toxicity at 60 months is currently underway.

Citation Format: Dautruche A, Belin L, Cottu P, Bontemps P, Lemanski C, De La Lande B, Baumann P, Missohou F, Levy C, Peignaux K, Reynaud-Bougnoux A, Denis F, Gobillion A, Ady Vago N, Fourquet A, Kirova Y. Radiotherapy associated with concurrent bevacizumab in patients with non-metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-10-17.
Abstract P1-11-01: The effect of close and positive surgical margins on 10-year local recurrence and survival outcomes in women treated with breast conserving surgery plus adjuvant radiotherapy
Authors: Tyler S , Truong P , Lesperance M , Nichol A , Baliski C , Warburton R , Tyldesley S
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P1-11-10: Clinical applications of near infra-red imaging system for localization of non-palpable breast lesions in breast conserving surgery
Authors: Jung S-Y , Lee S , Kim SK
Published: March 2017

Backgrounds: Localization of non-palpable breast lesions is important for obtaining tumor-free resection margin and achieving better cosmetic outcome. Near infra-red (NIR) imaging system has been introduced for localization in breast surgery. This study aimed to evaluate the feasibility of localization using NIR imaging system in breast conserving surgery (BCS) (ClinicalTrials.gov identifier: NCT 02172989/ NCT02473159).

Materials and Methods: Between June 2014 and October 2015, 20 women with benign neoplasm and 5 patients with early breast cancer were enrolled and underwent BCS using NIR imaging system. Before surgery, Indocyanine green was injected intratumoraly in benign lesions and peritumoraly for resection margins in early breast cancer. Their pathologic results for resection volume and re-excision rate were compared with those of the patients with 99 benign neoplasm and 203 early breast cancer who were treated with BCS by conventional method, respectively.

Results: In the patients with benign lesions, the mean size in sonography was 1.48±0.98 cm in NIR group and 1.32±0.96cm in conventional group (P=0.4). There was no difference of pathologic lesion size and excised specimen size between these groups (1.57±0.78 cm vs 1.42±0.80 cm in pathologic lesion size; P=0.63, 4.28± 0.48 cm vs 4.15±1.37 cm in specimen size; P=0.73). In NIR group, the ratio of excised specimen/lesion was lesser than that of conventional group (3.19 ±1.40 vs 4.31±3.86; P=0.008). In addition, positive margin rate after BCS in early breast cancer patients was 0% in NIG group and 19.7% in conventional group. And re-excision rate was 0% and 4.4%, respectively.

Conclusions: This study showed that localization using NIR image system could be a feasible method to obtain safe resection margins and optimum resection volumes in patients undergoing breast conserving surgery.

This research was supported by National Cancer Center Grant NCC-1410202-1 & NCC-1410202-2 by the National Cancer Center, Republic of Korea.

Citation Format: Jung S-Y, Lee S, Kim SK. Clinical applications of near infra-red imaging system for localization of non-palpable breast lesions in breast conserving surgery [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-11-10.
Abstract P2-01-19: SentiNot: A way to avoid sentinel node biopsy (SNB) in patients with a preoperative diagnosis of ductal cancer in situ (DCIS)
Authors: Karakatsanis A , Olofsson HM , Eriksson S , Andersson Y , Bergkvist LÅ , Mohammed I , Sundqvist M , Abdsaleh S , Olofsson Bagge R , Sund M , Wärnberg F
Published: March 2017

Background

The risk for node metastasis in preoperative diagnosis of DCIS is low. ASCO guidelines suggest that SNB could be performed when mastectomy is planned or in those cases where the probability of upgrading to invasive cancer postoperatively is high. Despite that, SNB is performed almost in 54% of DCIS procedures in the Uppsala-Örebro Region. Thus, morbidity and resources have to be balanced against the risk of a reoperation.

Methods

Patients with a preoperative diagnosis of DCIS grade 3, grade 2 ≥20mm or planned for a mastectomy will be included. Sienna+ is injected in the breast at the first operation. If the specimen contains invasive cancer, a SNB is performed in another session. Sienna+ can be detected in the axilla at least four weeks after the injection. Endpoints of the trial are the feasibility of detection of the SN as well as how many SNBs are avoided.

Results

In the first 34 cases, six had invasive breast cancer. On reoperation (median 29 days, iqr 10) SNB was successful in four cases with SPIO, one with Tc99 and three cases with blue dye. Totally, the combination of SPIO and blue dye was successful in all cases. No metastases were found.

Patient characteristics Total cohort (N=34)Group with IBC (n=6)Age (yrs)58.6 (54.9, 62.9)60.2 (47.4, 72.9)Size (mm)40.0 (31.2, 62.9)57.7 (27.2, 88.1)DCIS grade29 (26.5%)2 (33.3%) 323 (67.6%)4 (66.7%) na2 (5.9%)0PalpableYes30 (88.2%)1 (16.7%) No4 (11.8%)5 (83.3%)BCSYes22 (64.7%)3 (50%) No12 (35.3%)3 (50%)Transcutaneous counts at the end of the operation266 (196,336)300 (126,474)

Conclusion

It is possible to load the SN with SPIO and reoperate within 4 weeks from the first operation. A rough 83,4% of all patients with DCIS who would have undergone SNB avoided it. Our preliminary results show that 5,6 SNB was avoided for each patient that was operated. SN was detected in all cases with a combination of SPIO and blue dye, but only in 66,7% SPIO. It seems that increased experience with SPIO will increase the effectivity of this procedure.

Citation Format: Karakatsanis A, Olofsson HM, Eriksson S, Andersson Y, Bergkvist LÅ, Mohammed I, Sundqvist M, Abdsaleh S, Olofsson Bagge R, Sund M, Wärnberg F. SentiNot: A way to avoid sentinel node biopsy (SNB) in patients with a preoperative diagnosis of ductal cancer in situ (DCIS) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-19.
Abstract P2-01-23: Long-term follow-up of persistent breast dermopigmentation after sentinel lymph node identification using superparamagnetic iron oxide particles (SIENNA+®)
Authors: Hannebicque K , Boulanger L , Bogart E , Giard S , Chauvet MP , Houpeau JL
Published: March 2017

Background

The French Sentimag study evaluated a non-invasive method for the localization of breast cancer sentinel lymph nodes (SLN) using SIENNA+®, a superparamagnetic iron oxide particles (SPIO), in addition to conventional techniques (radiotracer and blue dye). SIENNA+® was injected subcutaneously into the breast and detected by the SENTIMAG® handheld magnetometer probe. The results showed a good SLN identification performance but a skin discoloration was noted during this study after the SIENNA+® injection. This aim of this study was to assess the long-term duration and appearance of this dermopigmentation.

Methods:

56 patients had participated in Sentimag study in our Center, 6 patients who had undergone mastectomy were excluded. We selected 50 patients who had undergone breast conservative surgery. For these patients, SLN localization was performed by both the conventional method (radiotracer and /or blue dye) and magnetic tracer, SIENNA+®. 47 patients were reviewed retrospectively from January 2015 to April 2015, 1.5 to 2 years after surgery and were assessed for skin discoloration.

Results :

Of the 47 patients, a dermopigmentation, from grade 1 (light yellowing) to grade 3 (dark browning) remained visible at the site of injection of SIENNA+® after 20.2 months [14.4-25.9] in 36.1% of the patients (17/47). 6.4% of 47 patients seen had grade 3 skin discoloration and 29.7% had grade 1 or 2 skin discoloration. Interestingly, no patients reported that persistent staining was a cosmetic or psychological problem.

Conclusions :

The use of SIENNA+® appears as an alternative method to radioisotopes for SLN identification in early breast cancer, but it may result in a prolonged-dermopigmentation at the injection site. To avoid dermopigmentation, it would be interesting to compare different techniques of SIENNA+® injection into the breast (intra-tumoral injection or a deeper periareolar injection) through a randomized trial.

Citation Format: Hannebicque K, Boulanger L, Bogart E, Giard S, Chauvet MP, Houpeau JL. Long-term follow-up of persistent breast dermopigmentation after sentinel lymph node identification using superparamagnetic iron oxide particles (SIENNA+®) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-23.
Abstract P2-01-31: Validation of novel diagnostic kits using the semi-dry dot-blot method for detecting metastatic lymph nodes in breast cancer; distinguishing macrometastases and micrometastases
Authors: Otsubo R , Hirakawa H , Oikawa M , Inamasu E , Baba M , Matsumoto M , Yano H , Kinoshita N , Abe K , Fukuoka J , Nagayasu T
Published: March 2017

Background: The semi-dry dot-blot (SDB) method is a diagnostic procedure for detecting lymph node (LN) metastases. Metastases are confirmed by the presence of cytokeratin (CK) in lavage fluid of sectioned LNs that contain anti-pancytokeratin antibody, based on the theory that epithelial components such as CK are not found in normal LNs. We evaluated two novel SDB kits that use the newly developed anti-CK19 antibody for diagnosing LN metastases in breast cancer.

Methods: We obtained 159 LNs dissected from 93 breast cancer patients from July 2013 to December 2015 at Nagasaki University Hospital, including 38 dissected axillary LNs and 121 sentinel LNs, sliced at 2-mm intervals and washed with phosphate-buffered saline. The suspended cells in the lavage fluid of sliced LNs were centrifuged and lysed to extract protein. This extracted protein was used with a low-power and a high-power kit to diagnose LN metastasis. The washed LNs were blindly diagnosed by pathologists using hematoxylin and eosin (H&E) stain. Diagnoses based on the kit were compared with their H&E counterparts.

Results: Of the 159 LNs, 68 were assessed as positive and 91 as negative by permanent pathological examination with H&E. Sensitivity, specificity, and accuracy of the low-power kit for detecting LN metastases was 83.8%, 100%, and 93.1%, respectively. In 11 false-negative cases, there were nine micrometastases, producing a sensitivity of 96.4% for detecting macrometastases. Sensitivity, specificity, and accuracy of the high-power kit for detecting LN metastases was 92.6%, 92.3%, and 92.5%, respectively. Combining the low- and high-power kit results, sensitivity, specificity and accuracy for distinguishing macrometastases from micrometastases was 94.5%, 95.2%, and 95.0%, respectively. Diagnosis was achieved in approximately 20 min using the kits, at a cost of less than 25 USD.

Conclusions: The kits in our study were accurate, quick, and cost-effective in diagnosing LN metastases without the loss of LN tissue. The kits' ability to distinguish macrometastases from micrometastases was excellent, which is important, clinically.

Citation Format: Otsubo R, Hirakawa H, Oikawa M, Inamasu E, Baba M, Matsumoto M, Yano H, Kinoshita N, Abe K, Fukuoka J, Nagayasu T. Validation of novel diagnostic kits using the semi-dry dot-blot method for detecting metastatic lymph nodes in breast cancer; distinguishing macrometastases and micrometastases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-31.
Abstract P2-01-34: Identification and biopsy of sentinel lymph nodes using intradermal microbubbles and contrast-enhanced ultrasound (CEUS) in pre-operative breast cancer patients: Early collective experience of the UK Microbubble Group
Authors: Cox KL , Sharma N , Leaver A , Lim A , Mills P , Weeks J , Sever A , Hashem M , DeSilva T
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P2-01-35: A one-day protocol with activities lower than 20 MBq for the detection of sentinel lymph nodes - Experience after 150 cases
Authors: Kolberg H-C , Afsah S , Winzer U , Akpolat-Basci L , Stephanou M , Liedtke C
Published: March 2017

Introduction:

Common protocols for the detection of sentinel lymph nodes (SLN) in early breast cancer often include injection of the tracer one day before surgery. In order to detect enough activity on the day of surgery, the applied activity in many protocols is as high as several hundred MBq. Even in common one-day protocols the activity applied is often up to 50 MBq. We developed a one-day protocol with a mean activity lower than 20 MBq in order to reduce radiation exposure for patients and staff. Here we are presenting our experience after 150 cases.

Material and methods:

150 patients with clinically and sonographically negative axilla (cN0) and no multicentricity underwent a SLN biopsy using a low-dose protocol performed on the day of surgery. After ultrasound-guided injection of the tracer (Technetium99) lymphoscintigraphy was performed in all cases. 7 minutes before the first cut 5 ml blue dye was injected in the region of the areola. Fresh-frozen sections of the SLN(s) were not performed.

Results:

In 149 of 150 patients (99.3%) at least one SLN could be identified by lymphoscintigraphy. The detection rate during surgery with combined tracers Technetium99 and blue dye was 100%. The mean applied activity was 17.8 MBq (9-20). A mean number of 1.3 (0-5) SLNs were identified by lymphoscintigraphy, a mean number of 1.7 (1-5) SLNs were removed during sentinel lymph node biopsy. 36 patients received a secondary axillary dissection according to the historical standard because of involved SLNs. In 11 cases (30.6%) additional involved lymph nodes were found.

Conclusion:

One-day protocols with an activity lower than 20 MBq are a safe alternative to two-day protocols with significantly higher radiation doses. Using Technetium99 and blue dye in a dual tracer approach, detection rates of 100% are possible in clinical routine with minimal radiation exposure for patients and staff. The number of removed lymph nodes, the rate of secondary axillary dissections and the number of cases with additional involved lymph nodes is not higher than in published trials.

Citation Format: Kolberg H-C, Afsah S, Winzer U, Akpolat-Basci L, Stephanou M, Liedtke C. A one-day protocol with activities lower than 20 MBq for the detection of sentinel lymph nodes - Experience after 150 cases [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-35.
Abstract P2-01-38: Factors that can be used to guide further axillary treatment following positive sentinel lymph node biopsy
Authors: McIntyre N , Murray J , FitzGerald SC , Murphy DS , Lannigan AK
Published: March 2017

This abstract was not presented at the symposium.
Abstract P2-02-03: Optimized prediction of deleterious missense mutations in BRCA1 and BRCA2 genes
Authors: Hart SN , Hoskin T , Shimelis H , Feng B , Lindor NM , Monteiro A , Iversen E , Goldgar DE , Suman V , Couch FJ
Published: March 2017

Approximately 15% of genetic screens for mutations in BRCA1 and BRCA2 identify Variants of Uncertain Significance (VUS). Primarily missense mutations, VUS are often difficult to interpret, leading to either uncertainty in how to properly counsel a patient or an unnecessary prophylactic surgery. Given the paucity of data for which missenses are classified as truly pathogenic, computational deleterious missense prediction (DMP) algorithms are used to predict whether a mutation is likely deleterious or neutral. Accuracy of DMPs can vary considerably and have only been calibrated on a relatively small number of missense mutations of demonstrable effect on protein function. In this study, the performance of 41 different DMPs was compared to functional data from 455 functionally characterized missense variants in BRCA1 and BRCA2. New optimized thresholds for classifying missense mutations as deleterious are presented for several existing models as well as a newly derived naïve voting method (NVM). The areas under the curve estimates for the NVM approach are between 0.889-0.922, much higher than previous methods. We estimate that the overall pathogenic potential of missense variants to be 6.8% for BRCA1 and 3.2% of BRCA2, but can be as high as 50% depending on protein location. Overall these results provide key insights into how to predict deleterious missense mutations in BRCA1 and BRCA2.

Citation Format: Hart SN, Hoskin T, Shimelis H, Feng B, Lindor NM, Monteiro A, Iversen E, Goldgar DE, Suman V, Couch FJ. Optimized prediction of deleterious missense mutations in BRCA1 and BRCA2 genes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-02-03.
Abstract P2-02-04: Li-Fraumeni syndrome in females with early onset breast cancer in a Mexican population
Authors: Gallardo-Alvarado LN , Cantu-De Leon DF , Tusie-Luna T , Tusie-Luna I , Diaz-Chavez J , Herrera EM , Chavez-MacGregor M , Bargallo-Rocha E , Villarreal C , Herrera.Montalvo LA , Segura-Kato YX
Published: March 2017

Background: Breast cancer in Mexican patients presents in average 10 year earlier compared to other populations. Among patients with TP53 mutations, breast cancer is the most common malignancy. In this study we aim to determine the rate of TP53 mutations among young Mexican breast cancer patients.

Methods: Breast cancer patients younger that 45 were retrospectively identified, only patients without BRCA1/2 mutations were included. Clinical records and pedigrees were reviewed. Next generation sequencing test for TP53 was performed from blood specimens. All pathogenic mutations were confirmed by Sanger sequencing and verified if were included in the IACR TP53 database.

Results: Among the 78 patients younger than 45yo evaluated and tested with next generation sequencing, we identified 5 patients with a TP53 mutation (6.4%). All were younger than 36 corresponding to a rate of 9.4% of mutations in this group of individuals (n = 53). Two, not previously described, frameshift mutations were found (c.291delC and c.273dupG) and three missense mutations (c.844C>T, c.517G>A, c.604C>T). A VUS c.672G>A that causes a silent mutation in a splicing-donor site was identified. All patients with a TP53 mutation had locally advanced disease and tumors were high grade and Her2 positive.

Conclusions: Among Mexican women younger than 45yo, the rate of TP53 mutations was higher than in other populations where it's estimated to be 1%. Among patients younger than 36 the proportion was even higher. All patients had a family history suggestive of Li-Fraumeni syndrome. The VUS found in our series needs a deeper analysis (family segregation, structure and function of the resulting protein). Our results support the international recommendation of performing molecular testing for TP53 in breast cancer patients younger than 35 years. Identification of patients with TP53 mutation has important prognostic, therapeutic and quality of life implications for the proband in addition of the risk reduction strategies and intensive surveillance recommended in their families.

Citation Format: Gallardo-Alvarado LN, Cantu-De Leon DF, Tusie-Luna T, Tusie-Luna I, Diaz-Chavez J, Herrera EM, Chavez-MacGregor M, Bargallo-Rocha E, Villarreal C, Herrera.Montalvo LA, Segura-Kato YX. Li-Fraumeni syndrome in females with early onset breast cancer in a Mexican population [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-02-04.
Abstract P2-03-11: Genomic pattern of breast carcinomas carrying mutations of non-BRCA homologous recombination genes
Authors: Lin P-H , Kuo W-H , Wang M-Y , Lo C , Lin C-H , Lu Y-S , Chiu C-F , Huang C-S
Published: March 2017

Background

BRCA1 and BRCA2 are involved in the homologous recombination (HR) double-strand DNA break repair and genomic patterns of breast tumors with defective BRCA are characterized by increased genomic instability. The pre-clinical and clinical studies show that tumors with defective BRCA or other HR genes can response to platinum and PARP inhibitors. However, the genomic pattern of tumors carrying mutations of non-BRCA HR genes are not investigated.

Methods

Genomic patterns of breast carcinomas were performed by comparative genomic hybridization (CGH) array containing 60000 probes covering the whole genome with an average spacing of 40kb. The frequency of gains and losses for each regions detected by probes was calculated by ratio thresholds of 0.25 and -0.25, respectively. Large-scale genomic structural aberration was defined as the region of gains and losses of at least 10Mb. We analyzed the difference of large-scale aberration, including numbers, length and specific regions, between tumors with BRCA mutation (mtBRCA), non-BRCA HR mutation (mtHR) and wild type.

Results

We examined 41 breast carcinomas, including 15 cases with BRCA mutations, 14 with non-BRCA HR gene mutations and 12 without mutations (control). The 14 non-BRCA HR gene were 1 ATM, 1 BRIP1, 1 BARD1, 1 FANCA, 2 FANCB, 1 FANCI, 1 PALB2, 2 RAD50, 2 RAD51C and 2 RAD51D. The number and length of large-scale genomic structural aberration of mtBRCA tumors were significantly higher than wild type tumors (number p=0.005; length p=0.005), indicating CGH can distinguish the mtBRCA from control tumors. We then checked the mtHR tumors, which also revealed significantly increased number and longer length of structural aberrations compared to wild type tumors (number p=0.035; length p=0.022), but were not different from mtBRCA tumors (number p=0.204; length p=0.425). Among the specific regions on chromosomes, mtBRCA and mtHR tumors contained similar genomic aberration regions but different from wild type tumors. The most frequent aberration regions of mtBRCA and mtHR tumors are chromosome 6p22.1-p25, 6q21-q27, 8q11.1-q24, 11p11.2-p14.1, 11q, 12p and 19p, which are less revealed in the wild type (all p value <0.05).

Conclusions

Our study demonstrated a direct evidence that increased genomic instability were the common characteristics of mtBRCA and non-BRCA mtHR tumors. In addition, we identify the specific genomic patterns of mtBRCA and mtHR tumors, which can be a biomarker indicating HR deficiency and response to platinum and PARP inhibitors.

Citation Format: Lin P-H, Kuo W-H, Wang M-Y, Lo C, Lin C-H, Lu Y-S, Chiu C-F, Huang C-S. Genomic pattern of breast carcinomas carrying mutations of non-BRCA homologous recombination genes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-03-11.
Abstract P2-04-11: Promotion of immunogenicity using epigenetic modulation and immune checkpoint inhibition in mouse models of breast cancer
Authors: Roussos Torres ET , Ma H , Armstrong T , Connolly R , Stearns V , Jaffee EM
Published: March 2017

This abstract was not presented at the symposium.
Abstract P2-04-22: Porous silicon microparticle potentiates anti-tumor immunity
Authors: Shen H , Xia X , Guevara M , Li Z
Published: March 2017

This abstract was not presented at the symposium.
Abstract P2-04-24: Changes of tumor-infiltrating lymphocytes and programmed death-ligand1 positivity after neoadjuvant chemotherapy in patients with locally advanced breast cancer
Authors: Choi YJ , Lee JH , Moon SY , Choi JY , Jung SP , Bae JW , Park KH
Published: March 2017

Background

Recently, the balance in immune system between immune surveillance and tolerance is known to be associated with the prognosis of breast cancer patients. The aim of this study was to investigate changes of tumor-infiltrating lymphocytes (TILs) and programmed death-ligand1 (PD-L1) status after neoadjuvant chemotherapy (NAC) and their impact on recurrence in patients with locally advanced breast cancer.

Methods

Paired samples (before and after NAC) of triple negative or HER2+ breast cancer tissue were obtained from clinical stage II or III patients (n=39) undergoing NAC and subsequent breast resection. The assessment of immunohistochemical (IHC) staining for PD-L1 were performed. Immunostaining of forkhead box P3 (Foxp3) and CD4/CD8 were performed for subtyping of TILs in triple negative breast cancer (TNBC) only. Clinicopathologic data including baseline characteristics, tumor response and recurrence were reviewed.

Results

Proportion of PD-L1 (+) tumor cells in pre-chemotherapy tissue was 20% (5/25) in HER2+ and 28.6% (4/14) in TNBC. It could not predict pathologic complete response. Most post-chemotherapy tissue (21/24) showed same PD-L1 positivity with pre-chemotherapy tissue. The rest showed the decreased PD-L1 positivity after NAC.

In cases of TNBC, the increased number of CD8+ T cells was significantly associated with PD-L1 positivity in pre-chemotherapy tissue. (p=0.001) Foxp3+ T cell proportions decreased significantly (p=0.046) and CD8+/Foxp3+ T-cell ratio increased significantly (p=0.023) after NAC. The patients with increased number of CD8+ T cells after NAC had a tendency to live longer without recurrence compared to patients with decreased CD8+ T cells (62.3 vs 38.1 months, p=0.158).

Conclusion

Our data provides the clinical evidence that PD-L1 positivity are associated with CD8+ T cell proportion and increased CD8+ T cells after NAC might be good prognostic marker. The role of immunologic balance as a prognostic marker for recurrence must be evaluated in future study.

Citation Format: Choi YJ, Lee JH, Moon SY, Choi JY, Jung SP, Bae JW, Park KH. Changes of tumor-infiltrating lymphocytes and programmed death-ligand1 positivity after neoadjuvant chemotherapy in patients with locally advanced breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-04-24.
Abstract P2-04-26: Identifying patient-specific neoepitopes for cell-based and vaccine immunotherapy across breast cancer classifications reveals rarely shared recurrent neoepitopes
Authors: Nguyen A , Sanborn JZ , Vaske CJ , Rabizadeh S , Niazi K , Soon-Shiong P , Benz SC
Published: March 2017

Introduction: Targeted therapies for breast cancers such as trastuzumab and everolimus have durable clinical benefits for patients that express the relevant biomarkers (HER2 and mTOR respectively). Triple negative breast cancer patients lack these biomarkers and are left with few options. Recent advances in immunotherapy agents against PD-1/CTLA4 for patients with melanoma have yielded amazing clinical benefits for a subset of patients and may have similar results in breast cancer patients, but again the vast majority of patients still undergo disease progression. We analyzed whole genome sequencing (WGS) and RNA sequencing data from The Cancer Genome Atlas (TCGA) to identify neoepitopes among breast cancer patients that could be used to develop next-generation, patient-specific cancer immunotherapies. Neoepitopes are tumor specific markers that arise from mutations acquired from cancer and may represent a path to targeted therapies even in triple negative breast cancers.

Results: We analyzed 99 breast cancer patients from TCGA, containing a mixture of PR+/HER2+/ER+ and TNBC classifications. These breast cancer patient samples were selected by the availability of whole genome sequencing (WGS) data, RNA-sequencing data as well as clinical outcome data. We identified an average of 680 potential neoepitopes per patient based solely on WGS data. To further refine and select high quality neoepitopes we restricted these neoepitopes based on gene expression yielding an average of 304 expressed neoepitopes per patient. We predicted each patient's HLA typing using only omics data, which we then used to predict HLA-expressed neoepitope binding analysis resulting in an average of 11 high-quality tumor specific neoepitopes per patient. We identified few recurrent neoepitopes that were bound and expressed, indicating the need for a personalized medicine approach.

Conclusions: Within the TCGA dataset, the majority of neoepitopes among patients with breast cancer were unique to each patient. Rarely within subsets of breast cancers such as HER2+, we identify neoepitopes that are shared between patients. For breast cancer patients who do not respond to targeted therapies, high-throughput identification of neoepitopes could serve as the basis for the development of next-generation, patient-specific immunotherapies.

Citation Format: Nguyen A, Sanborn JZ, Vaske CJ, Rabizadeh S, Niazi K, Soon-Shiong P, Benz SC. Identifying patient-specific neoepitopes for cell-based and vaccine immunotherapy across breast cancer classifications reveals rarely shared recurrent neoepitopes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-04-26.
Abstract P2-05-22: Prognostic significance of nuclear factor kappa B in node-negative breast cancer is most pronounced in luminal B breast cancer
Authors: Schmidt M , Madjar K , Heimes A-S , Battista M , Lebrecht A , Almsetdt K , Hasenburg A , Rahnenführer J , Hengstler JG
Published: March 2017

Background: The importance of the cellular as well as the humoral immune system is increasingly recognized in breast cancer. The transcription factor nuclear factor kappa B (NFKB1) plays an important role in immune cell development. We examined the prognostic significance of NFKB1 in node-negative breast cancer.

Methods: Microarray based gene-expression data for NFKB1 (209239_at) were analysed in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) of node-negative breast cancer patients not treated with adjuvant therapy (n=824). A meta-analysis of previously published cohorts was performed using a random effects model. Intrinsic subtypes were determined using gene-expression data. Prognostic significance of NFKB1 for metastasis-free survival (MFS) was examined in the whole cohort, in estrogen receptor (ER) positive as well as ER negative patients, and in different intrinsic subtypes: luminal A, liminal B, basal-like, HER2-enriched (HER2-E), and normal-like. Independent prognostic relevance was analysed using multivariate Cox regression.

Results: Higher RNA expression of NFKB1 was related to better MFS in a meta-analysis of the whole cohort (HR 0.48, 95% CI 0.34-0.67, P<0.0001). NFKB1 was significantly associated with MFS only in ER positive (HR 0.41, 95% CI 0.24−0.69, P=0.0008) but not in ER negative (HR 0.76, 95% CI 0.39−1.48, P=0.4245) patients. Regarding intrinsic subtypes, the prognostic significance of NFKB1 was most pronounced in luminal B breast cancer (HR 0.40, 95% CI 0.17−0.93, P=0.0338) as compared to luminal A (HR 0.67, 95% CI 0.16−2.73, P=0.5738), basal-like (HR 0.67, 95% CI 0.29−1.56), P=0.3484), HER2-E (HR 0.70, 95% CI 0.25−2.00, P=0.5083), and normal-like (HR 0.49, 95% CI 0.18−1.32, P=0.1579) breast cancer. However, NFKB1 failed to show independent prognostic significance (HR 0.72, 95% CI 0.42-1.24, P=0.235) in multivariate analysis. Only histological grade of differentiation (HR 2.06, 95% CI 1.27-3.35, P=0.003) and tumor size (HR 1.58, 95% CI 1.01-2.48, P=0.045), but neither age nor HER2 status nor hormone receptor status maintained an independent prognostic association with MFS.

Conclusions: The transcription factor NFKB1 shows prognostic significance in node-negative breast cancer. Higher expression of NFKB1 is associated with improved outcome. The prognostic impact of NFKB1 differs between intrinsic subtypes and is most pronounced in luminal B breast cancer.

Citation Format: Schmidt M, Madjar K, Heimes A-S, Battista M, Lebrecht A, Almsetdt K, Hasenburg A, Rahnenführer J, Hengstler JG. Prognostic significance of nuclear factor kappa B in node-negative breast cancer is most pronounced in luminal B breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-22.
Abstract P2-05-37: In-situ hybridization of microRNA and support vector machines–based prognostic classifiers for breast cancer
Authors: Cao Z , Yao L , Hu X , Zhang Z , Shao Z
Published: March 2017

Purpose: We plan to use a tissue microarray-based microRNA(miRNA) detection by in situ hybridization with LNA probe and support vector machine on base of data mining to construct the Prognostic model for breast cancer and triple negative breast cancer (TNBC).

Methods: Combining the BreastMark miRNA database and papers published, we chose candidate miRNAs. Then a tissue microarray-based miRNA detection in situ hybridization with LNA probe was used to detect miRNA expression in 445 breast cancer tissue. Univariate analysis with Kaplan-Meier identified independent prognostic factors, 445 patients was divided into the training set and validation set (70% VS 30%) by software R(version 3.2.3), then support vector machine on base of data mining was used to construct the Prognostic model for breast cancer and triple negative breast cancer via software R and predict.svm(e1071).

Results: 15 miRNAs were detected from 445 breast cancer tissue and univariate analysis with Kaplan-Meier identified significant prognostic miRNAs: miR-361-5p, miR-301a, miR-223, miR-421, miR-454, miR-493 were the independent prognostic factors for DFS. By using data mining technique, we combined clinical factors(stage, tumor size, lymphnode status, molecular subtype) and miRNAs mentioned above to establish the personalized predictive mathematical models SVM-BC and SVM-TNBC.

In the training set and validation set of SVM-BC model, the AUC value of ROC curve for DFS were 0.86,0.83. The total accuracy,sensitivity,specificity of SVM-BC model for DFS were 94%,73%,99% and 84%,57%,92% in the training set and validation set. The SVM-BC model can divide breast cancer patients into high-risk and low-risk groups, and 5-year survival rates for low-risk patients were higher than that for high-risk patients(96.8% VS 39.3%, p<0.001).

In the training set and validation set of SVM-TNBC model, the AUC value of ROC curve for DFS were 0.84,0.86. The total accuracy,sensitivity,specificity of SVM-TNBC model for DFS were 90%,71%,97% and 84%,55%,94% in the training set and validation set. The SVM-TNBC model can divide breast cancer patients into high-risk and low-risk groups, and 5-year survival rates for low-risk patients were higher than that for high-risk patients(93.9 % VS 23.5%, p <0.001).

Conclusion: The Prognostic model basing of tissue microarray-based miRNA detection in situ hybridization with LNA probe and support vector machine for prognosis can effectively predict the prognosis of breast cancer and TNBC.

Citation Format: Cao Z, Yao L, Hu X, Zhang Z, Shao Z. In-situ hybridization of microRNA and support vector machines–based prognostic classifiers for breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-37.
Abstract P2-06-01: Non-genetic risk factors improve accuracy of breast cancer risk assessment for women at high familial risk: Comparison of risk estimation models using the prospective family study cohort (ProF-SC)
Authors: Terry MB , Phillips K-A , Liao Y , MacInnis RJ , Dite GS , Daly MB , John EM , Andrulis IL , Buys SS , Buchsbaum R , Hopper JL
Published: March 2017

This abstract was withdrawn by the authors.
Abstract P2-07-03: Insulin and breast cancer risk: Novel insights from mammographic density analyses
Authors: Borgquist S , Rosendahl AH , Czene K , Bhoo-Pathy N , Dorkhan M , Hall P , Brand JS
Published: March 2017

Background: Insulin has been suspected to influence breast cancer risk because of its mitogenic effects and impact on sex hormone levels. Epidemiological studies investigating breast cancer occurrence in insulin-treated patients with diabetes have produced conflicting results, but were often underpowered and lacked adequate control for important confounders.

Purpose: To investigate the impact of insulin treatment on mammographic density (MD) as intermediate phenotype for breast cancer risk, and to further explore causation by analyzing associations with a polygenic risk score (PRS) incorporating 18 single nucleotide polymorphisms (SNPs) associated with fasting insulin levels.

Design: We conducted a matched cohort study within a Swedish screening-based cohort including insulin-treated type 1 (T1D, N=122) and type 2 (T2D, N=237) diabetes patients and up to 5 non-diabetic women matched on birth year (N=1,780). Associations between diabetes status and duration of insulin use with volumetric mammographic density were analyzed using general linear models adjusting for a comprehensive set of potential confounders. PRS analyses were performed in an independent sample of non-diabetic women (N=9,437) from the same cohort.

Results: In multivariable analyses, T1D patients had higher percent (11.2 vs. 8.8%; P<0.001) and absolute dense volumes (66.6 vs. 60.8 cm3; P=0.09) and a lower absolute non-dense volume (513.2 vs. 617.7 cm3; P<0.001) compared to age-matched non-diabetics. Percent- and absolute dense volumes increased with increasing T1D duration, while no such trend was observed for the absolute non-dense volume. Similar associations but of smaller magnitude, were found in insulin-treated T2D patients. Genetically predicted higher fasting insulin levels among non-diabetes women were associated with increased percent and absolute dense volumes (% change per sd increase in PRS = 0.8 (0.0-1.6) and 0.9 (0.1-1.8) respectively), but no difference in absolute non-dense volume.

Conclusions: Our results demonstrate higher mammographic density among insulin-treated diabetes patients, and genetic analyses support an effect of insulin on volumetric mammographic density. Further studies into how the observed MD differences translate into breast cancer risk are warranted.

Citation Format: Borgquist S, Rosendahl AH, Czene K, Bhoo-Pathy N, Dorkhan M, Hall P, Brand JS. Insulin and breast cancer risk: Novel insights from mammographic density analyses [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-07-03.
Abstract P2-07-06: Obesity, dyslipidemia, and diabetes as risk factors for trastuzumab-related cardiotoxicity in breast cancer patients
Authors: Aseyev O , Johnson C , Turek M , Stadnick E , Law A , Gosh N , Dent S
Published: March 2017

Background. Clinical trials have demonstrated an increased risk of cancer treatment related cardiac dysfunction (CTCD) during trastuzumab(H) therapy. Diabetes, dyslipidemia, and obesity are also known risk factors for cardiovascular disease. The primary objective of this study was to evaluate the incidence of asymptomatic drop in left ventricular ejection fraction (AD-LVEF) and symptomatic CTCD (S-CTCD) in women with BC and co-morbidities receiving H, referred to a dedicated cardio-oncology clinic (COC).

Methods. This was a retrospective cohort study of women with BC (all stages) referred to The Ottawa Hospital COC between 2008 and 2015, who received chemotherapy (CT) and H. Data collected included: demographics, reason for referral, cardiac testing (MUGA/ECHO) co-morbidities (diabetes, dyslipidemia) and cardiac outcomes. Obesity defined as body mass index > 30. Symptomatic CTCD include SOB, PND, orthopnea, peripheral edema, congestive heart failure. Asymptomatic drop in LVEF defined as decrease of at least 15% from baseline; normal LVEF, or a decrease of at least 10% in LVEF, less than 53%.

Results. Chemotherapy (A-CT) followed by H, 62 received H without A-CT. 139 patients with no history diabetes, dyslipidemia, or obesity, referred with AD-LVEF (68%), with S- CTCD (30%), pre-CT assessment (2%). Obesity (O) pre-existing co-morbidity in 63 (26%) patients, (20 (32%) with S-CTCD, 40 (63%) referred with AD-LVEF, 3(5%) referred for pre-CT assessment). Dyslipidemia (L) – 52 (21%); referred with S-CTCD 15; 29%), with AD-LVEF 31 (60%), pre-CT assessment 6 (11). Diabetes (D) – 29 (12%) - (6 (21%) with S-CTCD, 19 (66%) referred with AD-LVEF, 4(13%) referred for pre-CT assessment). Combination of two or three conditions significantly increase incidence of S-CTCD: O+L – 67%, O+D – 69%, O+L+D – 72%. Combination of obesity and other conditions significantly increase incidence of S-CTCD: O+L – 67%(Relative Risk -2.2, p=0,04), O+D – 69% (RR-2.3, p=0,02), O+L+D – 72% (RR-2.4, p=0,08).

Conclusion. The combination of two or three co-morbidities significantly increases the incidence of S-CTCD. BC patients experiencing CTCD with pre-existing history of diabetes, dyslipidemia, and obesity may require more proactive strategies for prevention, detection and treatment of cardiotoxicity during trastuzumab-based treatment.

Citation Format: Aseyev O, Johnson C, Turek M, Stadnick E, Law A, Gosh N, Dent S. Obesity, dyslipidemia, and diabetes as risk factors for trastuzumab-related cardiotoxicity in breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-07-06.
Abstract P2-07-13: TP53 gene polymorphisms (c.[215G>C]) in breast cancer patients and predisposition to family cancers- Single center experience
Authors: Huszno J , Grzybowska E , Nycz Bochenek M , Pamula Pilat J , Tecza K , Nowara E
Published: March 2017

Introduction: Somatic mutations in the TP53 gene are one of the most frequent alterations in human cancers, and germline mutations are the underlying cause of Li-Fraumeni syndrome, which predisposes to a wide spectrum of early-onset cancers. The aim of this study was to evaluate the association between TP53 gene polymorphisms (c.[215G>C]) and predisposition to family cancers. Methods: We reviewed the medical records of 89 (21% TP53 gene homozygotes and 79% heterozygotes) breast cancer patients who were diagnosed and treated in COI in Gliwice. The history of family cancers was colected from medical history. Mutation profile was assessed by RFLP-PCR technique. We evaluatedthe presence ofpolymorphism TP53 (c.[215G>C]). Statistical analysis was carried out using STATISTICA 7 software. Results: Cancers in family history were detected in 72% of pts with TP53 polymorphisms and they were observed insignificantly more often in heterozygotes than in homozygotes (76% vs. 58%, p=0.153). The most frequently reported cancers were: breast cancer (33%), lymphoma (17%), colorectal cancer (9%), OUN cancer (8%), gastric cancer (8%), pancreatic cancer (7%), ovarian cancer (6%) and renal cancer (3%). In analyzed group, renal cancers in family were detected more frequently in TP53 homozygotes than in heterozygotes (16% vs. 0, p=0.008). Similarly, there was also observed tendency to the presence of colorectal cancer in TP53 homozygotes (11% vs. 0, p=0.193). Ovarian cancers and cholangiocarcinomas in family were also observed insignificantly more often in homozygotes than in heterozygotes (7% vs. 0, p=0.580) and (5% vs. 1%, p=0.383). There was no association between number of cancers in family and TP53 polymorphisms (47% vs. 43%, p=0.797). Conclusion: TP53 polymorphism (c.[215G>C]) predisposed to development renal and colorectal cancers (TP53 homozygotes) and ovarian cancer or cholangiocarcinoma (TP53 heterozygotes) in family.

Citation Format: Huszno J, Grzybowska E, Nycz Bochenek M, Pamula Pilat J, Tecza K, Nowara E. TP53 gene polymorphisms (c.[215G>C]) in breast cancer patients and predisposition to family cancers- Single center experience [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-07-13.
Abstract P2-08-11: An orally bioavailable selective estrogen receptor downregulator
Authors: Wang G , Liu J , Zheng S , Miele L , Wiese T , Zhong Q , Guo S
Published: March 2017

Orally bioavailable selective estrogen receptor downregulators (SERDs) may offer greater systemic drug exposure, improved clinical efficacy, and more durable treatment outcome for breast cancer patients with disease progression following antiestrogen or aromatase inhibitor therapy. We report the design and synthesis of ZB716, a C-3 position boronic acid modified fulvestrant, which behaves as a steroidal SERD suitable for oral administration. ZB716 binds to ERa competitively at an IC50 of 4.1 nM as compared to 3.9 nM for fulvestrant, and it effectively downregulates ERa (IC50=12.7 nM) in both tamoxifen-sensitive (T47D) and tamoxifen-resistant (T47D/PKCa) breast cancer cells. It acts as an antiestrogen that exerts potent antiproliferative effects on tamoxifen-resistant breast cancer cells (MCF-7/TamR, T47D/PKCa, and T47D/Y537S). When orally administered to mice, rats, and Beagle dogs, ZB716 demonstrates superior oral bioavailability in all animal-based pharmacokinetic studies when compared to fulvestrant administered by subcutaneous injection. More importantly, orally administered ZB716 was found to potently inhibit xenograft tumor growth in mice. These pre-clinical data strongly suggest that ZB716 is a promising SERD drug that could offer significant improvement over existing SERD regimen of Faslodex. ZB716 is being prepared in an IND application for phase 1 clinical trial in ER+, HER2- advanced breast cancer patients.

Citation Format: Wang G, Liu J, Zheng S, Miele L, Wiese T, Zhong Q, Guo S. An orally bioavailable selective estrogen receptor downregulator [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-08-11.