bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-06-09: Discovery of novel oridonin-derivatives for the treatment of metastatic breast cancer
Authors: Li D , Zhang Z , Ding Y , Zheng Z , Dong J , Kim H , Xu J , Chen H , Zhou J , Shen Q
Published: February 2018

Metastasis to other organs is the major cause of death from breast cancer. The 5-year survival rate is approximately 99% for localized breast cancer, but sharply drops to approximately 26% for patients with distant metastasis. However, there are currently no effective, targeted therapies available for treating metastatic breast cancer. Oridonin, a complex ent-kaurane diterpenoid isolated from Chinese traditional herb Rabdosia rubescens, has demonstrated great potential in the treatment of various human cancers. However, relatively low aqueous solubility and bioavailability limited its development into clinical applications. Herein, a number of novel nitrogen-enriched heterocyclic oridonin derivatives and dienone analogs such as YD0514, CYD0618, and CYD0686 have been generated from oridonin. These derivative analogs showed improved anti-proliferation effects against breast cancer cells, compared to oridonin. YD0514, CYD0618, and CYD0686 also displayed significant suppression of migration and invasion in MDA-MB-231 cell, a highly metastatic triple-negative breast cancer cell line. Furthermore, YD0514, CYD0618 and CYD0686 also inhibited the endothelial adhesion of GI101 and its derived, highly metastatic sublines, to the endothelium. We next found that YD0514, CYD0618, and CYD0686 can significantly inhibit the expression and phosphorylation of FAK and block the expression of integrin family members in those highly metastatic breast cancer cell lines. Further pathway analysis demonstrated that YD0514, CYD0618, and CYD0686 inhibited cellular motility potentially by decreasing RHOA/ROCK signaling pathway. Our findings suggest that novel oridonin-derivatives, YD0514, CYD0618, and CYD0686 have the great potential to be developed as effective therapeutics for the treatment of metastatic breast cancer. This work was supported by Grants P50 CA097007, and P30DA028821 (JZ) from the NIH, CPRIT (JZ), John Sealy Memorial Endowment Fund (JZ), DFI Grants from MD Anderson Cancer Center (QS), and Holden Family Research Grant in BC Prevention (QS).

Citation Format: Li D, Zhang Z, Ding Y, Zheng Z, Dong J, Kim H, Xu J, Chen H, Zhou J, Shen Q. Discovery of novel oridonin-derivatives for the treatment of metastatic 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 P3-06-09.
Abstract P3-08-04: Withdrawn
Authors: Hortobagyi G , Weaver DL , Solin L , Connolly J , Mittendorf E , Winchester DJ , Rugo H , Edge SB , Giuliano A
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P3-10-02: Presence of atypia in ductal lavage and risk of subsequent breast cancer in a prospective study
Authors: De Censi A , Cazzaniga M , Gandini S , Casadio C , Chiapparini L , Guerrieri-Gonzaga A , Macis D , Veronesi P , Bonanni B
Published: February 2018

Background: Atypical hyperplasia is considered a nearly obligate precursor of breast cancer and is associated with a higher risk of developing breast cancer (BC). Attempts to improve early detection of breast cancer and to provide individualized breast cancer risk assessment would greatly benefit from sampling cellular material from the target tissue. Ductal lavage (DL) is a minimally invasive technique which provides adequate material to detect atypical cells in mammary ducts. However, long term data of the association between atypia from ductal lavage and BC risk are lacking. We studied the prevalence of atypia in DL in different risk categories and its ability to predict BC development in women at risk. Methods: From March 2000 to July 2012 we performed DL in a consecutive series of 348 women with median age of 45 years (range 19-74) at increased BC risk based on the following characteristics: 5 yrs Gail model > 1.66% or > 10% probability of BRCA mutation (n = 155), history of contralateral BC (CBC, n = 161), presence of a BRCA pathogenic variant (n = 32). We analyzed the presence of atypical cells in the baseline specimen of ductal lavage and in repeated lavage and observed their evolution during follow-up. Results: The procedure was safe and well tolerated in most women, with pain and disconfort preventing the procedure in 5.4% of subjects. Overall, 126 (36%) women had atypia at baseline, with a prevalence of 32%, 39%, and 41% in the Gail, CBC and BRCA groups, respectively (p = 0.38). The overall prevalence of atypia considering all visits was 44% (range 36-51). After a median follow up of 6 years, cumulative BC events were 8% in women without atypia versus 14% in those with atypia (log-rank p = 0.08). In the highest risk groups (CBC and BRCA pathogenic variants), the number of BC events was 16 (21%) in women with atypia versus 11 (10%) in women without atypia (p = 0.02 after adjustment for age). Conclusions: Our findings suggest that cytologic atypia in the fluid obtained by DL predicts subsequent BC in women at increased risk, providing individual risk assessment. The reversal of atypia in DL should be evaluated as a surrogate biomarker of BC therapeutic prevention.

Supported by: Associazione Italiana per la Ricerca sul Cancro (AIRC), Lega Italina per la Lotta contro i Tumori (LILT), AVON Foundation for Women.

Citation Format: De Censi A, Cazzaniga M, Gandini S, Casadio C, Chiapparini L, Guerrieri-Gonzaga A, Macis D, Veronesi P, Bonanni B. Presence of atypia in ductal lavage and risk of subsequent breast cancer in a prospective 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 P3-10-02.
Abstract P3-13-01: Withdrawn
Authors: Robertson JFR , Morden JP , Dowsett M , Smith I , Bliss JM
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P3-13-02: Withdrawn
Authors: Cottu PH , D'Hondt V , Dureau S , Lerebours F , Desmoulins I , Heudel P , Duhouix F , Levy C , Mouret-Reynier M-A , Dalenc F , Frenel J-S , Jouannaud C , Venat-Bouvet L , Nguyen S , Ferrero J-M , Canon J-L , Grenier J , Vincent-Salomon A , Lemonnier J , Delaloge S
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P4-01-02: Choosing wisely: Radiographic surveillance after breast conservation therapy in HER2+ breast cancer
Authors: Everett A , Wallace AS , De Los Santos JF , Rocgue GB , Parker CS , Keene KS
Published: February 2018

Purpose/Objective(s): ASTRO Choosing Wisely campaign recommends no more than annual mammography after breast conservation therapy (BCT). HER2+ disease portends increased risk of locoregional recurrence in comparison to Luminal A disease. Our previous institutional practice included surveillance imaging every 6 months for the first 2-3 years after BCT. The purpose of this study is to evaluate surveillance imaging intervals as a means of detecting early locoregional recurrence at one institution.

Materials/Methods: Women with HER2+ locoregionally confined invasive breast cancer treated with lumpectomy and radiation as part of breast conservation therapy at one institution were retrospectively identified after IRB approval. Patient demographics, treatment, surveillance, and outcomes data were captured. BRCA+ patients or those without available surveillance follow-up at our institution were excluded. Surveillance period started after the last fraction of radiation was completed.

Results: In 86 women treated from 2008-2016, median age at diagnosis was 57, and 69% were Caucasian. Most patients were treated for Stage I-II invasive ductal carcinoma. All but one were treated with chemotherapy, with similar distribution between adjuvant and neoadjuvant regimens. Receptor status was as follows: ER+ 66%, PR+ 59%, ER+/PR+/HER2+ in 58%, ER-/PR-/HER2+ in 33%. Mammography +/- ultrasound was utilized, with infrequent use of magnetic resonance imaging. Median time from end of radiation to first surveillance imaging was 4 months. All women had 1 post-BCT imaging, with 2nd, 3rd, and 4th available in 91%, 85%, 73% respectively. Interval frequency between first 4 images was 6 months. No patients had expired at the time of analysis. Recurrence were identified in 2 women: 1 identified clinically after negative mammography, and 1 identified on mammography at 27 months.

Conclusion: While overall events are small, discordant biannual mammography did not identify locoregional recurrences in this biologically higher risk group in the first two years post-treatment. This data supports current guideline recommendations limiting surveillance breast imaging in patients undergoing breast conservation to an annual frequency.

Citation Format: Everett A, Wallace AS, De Los Santos JF, Rocgue GB, Parker CS, Keene KS. Choosing wisely: Radiographic surveillance after breast conservation therapy in HER2+ 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 P4-01-02.
Abstract P4-04-07: Characterization of the effects of estrogen receptor alpha Y537S and D538G mutations on receptor function and pharmacology
Authors: Blake RA , Hartman SJ , Kleinheinz TL , White J , Daly S , Goodwin R , Zhou W , Liang J , Wang X , O'Rourke M , Metcalfe C , Friedman L
Published: February 2018

The frontline therapy for estrogen receptor alpha (ERα) positive Breast Cancer (ER+BC) involves various forms of endocrine therapy, consisting of either Selective Estrogen Receptor Modulators (SERMs) or aromatase inhibitors. An emerging mechanism of ER+BC resistance to endocrine therapy, and consequently disease relapse, has been associated with a set of “hotspot” mutations in and near to helix-12 of the ERα ligand binding domain. Selective Estrogen Receptor Degraders/Down-regulators (SERDs), such as GDC-0810, AZD9496 and GDC-0927, represent a current major pharmacological strategy being applied to develop treatments for such resistant ER+BC. Here, we compare 2 of the most frequent ERα hotspot mutations (Y537S and D538G), with ERα wildtype (WT) and the ability of a set of ERα ligands (including GDC-0810, AZD9496 and GDC-0927) to bind, antagonize and degrade ERα. The concentration of each drug required to bind, antagonize or degrade ERα Y537S or ERα D538G was typically higher than that required for ERα WT. Importantly, ERα Y537S is resistant to estradiol stimulated protein degradation and 4-hydroxy-tamoxifen (a major active metabolite of tamoxifen) stabilizes ERα Y537S protein. This represents a potential mechanism of resistance of ERα Y537S ER+BC to Tamoxifen therapy.

Citation Format: Blake RA, Hartman SJ, Kleinheinz TL, White J, Daly S, Goodwin R, Zhou W, Liang J, Wang X, O'Rourke M, Metcalfe C, Friedman L. Characterization of the effects of estrogen receptor alpha Y537S and D538G mutations on receptor function and pharmacology [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 P4-04-07.
Abstract P4-09-05: Withdrawn
Authors: Poola I , Yue Q , Gillespie J , Shaaban A , Rao J , Sullivan P , Aguilar-Jakthong J , Sauter E , Ricci A
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P4-10-10: Withdrawn
Authors: Gates-Ferris K , Culler TA , Senter L , Ricci C , Huber D
Published: February 2018

This abstract was withdrawn by the authors.
Abstract P4-13-11: A complication analysis between complete and partial tissue expander coverage using autologous flaps in cases of immediate breast reconstruction
Authors: Kubo K , Hamahata A , Tozuka K , Tsuboi M , Hayashi Y , Takai K , Saito T , Sakurai H , Matsumoto H
Published: February 2018

Background:

To avoid tissue expander exposure following mastectomy flap necrosis, several methods for covering expander by autologous flap in cases of immediate breast reconstruction have been reported. These methods are classified into two groups, complete or partial expander coverage. Two methods have potential risks of postoperative complications following: insufficient lower pole expansion and cranial migration in complete coverage methods, and lateral migration in partial coverage methods. However, the comparisons of complication rates between these two methods have not been reported. This study aims to compare the incidence of expander exposure following mastectomy flap necrosis and expander migration between two methods.

Methods:

A retrospective review of 93 patients (99 breasts) who underwent immediate expander-based breast reconstruction was performed. Patients were divided into two groups, complete or partial expander coverage by autologous flaps. In both groups, expanders were placed into subpectral position. In partial coverage group, the lateral borders of pectralis major muscles were sutured to the mastectomy skin flaps. If the skin flap was too thin to be sutured, the serratus anterior muscro-fascial flap was dissected and sutured to the lateral border of pectralis major muscle to cover the expander completely. Allograft products were not used in both groups. Demographics, intraoperative findings, and postoperative complications were compared between two groups.

Results:

Of the 99 breasts, 56 underwent complete expander coverage and 43 underwent partial coverage. Mastectomy flap necrosis rate was higher in the complete coverage group (Complete 14.3% versus Partial 0%; p=0.0091), however, there was no incidence of expander exposure in both groups. Lateral migration rate was higher in the partial coverage group (Complete 0% versus Partial 9.3%; p=0.033). There was no difference in cranial migration rate between two groups (Complete 12.5% versus Partial 2.3%; p=0.133).

Conclusions:

The thinness of the mastectomy flaps was considered to provide the higher incidence of mastectomy flap necrosis in the complete coverage group. The complete expander coverage reduced lateral migration rate and prevented expander exposure in cases of mastectomy flap necrosis.

Citation Format: Kubo K, Hamahata A, Tozuka K, Tsuboi M, Hayashi Y, Takai K, Saito T, Sakurai H, Matsumoto H. A complication analysis between complete and partial tissue expander coverage using autologous flaps in cases of immediate breast reconstruction [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 P4-13-11.
Abstract P4-13-14: Risk of recurrence and death in breast cancer patients after delayed deep inferior epigastric perforator flap reconstruction
Authors: Adam H , Docherty Skogh A-C , Edsander Nord Å , Schultz I , Gahm J , Hall P , Frisell J , Halle M , de Boniface J
Published: February 2018

PURPOSE

Post-mastectomy reconstruction using the deep inferior epigastric perforator (DIEP) flap is increasingly performed in breast cancer patients. The procedure induces large tissue trauma and it has been hypothesized that the release of growth factors, angiogenic agonists and immunomodulating factors may reactivate dormant micrometastasis. The aim of our study was to contrast the risk of breast cancer recurrence in patients undergoing DIEP reconstruction to patients treated with mastectomy alone.

PATIENTS AND METHODS

We conducted a retrospective nested case-control study. Cases were defined as breast cancer patients operated with delayed DIEP reconstruction at Karolinska University Hospital, Sweden, between 1999-2013. Three controls, defined as breast cancer patients operated with conventional mastectomy without delayed reconstruction, were matched to each case based on age, tumour stage and year of mastectomy. The primary endpoint was breast cancer-specific survival. Survival analysis was carried out by Kaplan–Meier survival estimates and Cox proportional hazard regression analysis.

RESULTS

In all, 254 cases and 729 controls were included and had a median follow up of 134 and 122 months, respectively (p=0.004). Breast cancer recurrence occurred in 50 (19.7%) cases and 174 (23.9%) controls, respectively (p=0.171). Ten-year breast cancer-specific survival was 90.7% for cases and 85.2% in controls (p=0.067). The corresponding figures for 10-year overall survival was 89.6% and 80.0%, respectively (p<0.001). Higher tumor stage and positive axillary lymph nodes, but not DIEP reconstruction, were independent risk factors for death due to breast cancer.

CONCLUSION

Our findings did not support the hypothesis that breast cancer patients undergoing DIEP reconstruction would have a higher rate of breast cancer recurrence than patients undergoing mastectomy alone.

Citation Format: Adam H, Docherty Skogh A-C, Edsander Nord Å, Schultz I, Gahm J, Hall P, Frisell J, Halle M, de Boniface J. Risk of recurrence and death in breast cancer patients after delayed deep inferior epigastric perforator flap reconstruction [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 P4-13-14.
Abstract P5-08-01: Reconstructing the evolutionary paths of BIG 1-98
Authors: Lara-Gonzalez LL , Loi S , Ferrari D , Papenfuss A , Goode DL
Published: February 2018

We are reconstructing the dynamics of tumour growth, treatment response, and origins of resistance of the Breast International Group (BIG) 1-98 study to determine the evolutionary paths of non-responders.

We established the somatic alteration landscape of primary tumours collected at surgery from BIG 1-98 patients using targeted DNA sequencing of 287 genes of FFPE samples from 538 patients. Combined analysis of genetic and clinical data indicates increased genomic instability; TP53 mutations and copy number variations of 11q13 and 8p11 are associated with poor prognosis. We developed an in silico simulation framework to investigate if the non-responder outcome is due to (over)-treatment or intrinsic to evolutionary selection prior to diagnosis.

To reconstruct the evolutionary history of tumours, we created a computational multitype branching process that tracks the expansion of diverse clonal lineages as they acquire driver and passenger mutations that alter their proliferation and mutation rates. To account for the heterogeneity between patients, we created a fitting procedure based on the Cramer-von Misses statistic to find the likelihood of parameters of our computational model that recreate the mutational landscape and clinicopathological factors observed in each patient. Once the fitting procedure is done, we simulate the course of treatment following the study arm scheme accounting for the cell-cycle action mechanism of Tamoxifen and Letrozole.

Using our tool, we are characterising the range of tumour development scenarios covering different degrees of aggressiveness and genomic instability. Our computational model allows simulation of diverse adjuvant-schemes to predict optimised treatment regimes for validation in patient-derived tumour xenograft mouse models.

Citation Format: Lara-Gonzalez LL, Loi S, Ferrari D, Papenfuss A, Goode DL. Reconstructing the evolutionary paths of BIG 1-98 [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 P5-08-01.
Abstract P5-11-01: The accuracy of nomograms based on large dataset using clinico-pathologic variables for prediction of oncotype DX breast cancer recurrence score
Authors: Kim J-M , Ryu JM , Kim I , Choi HJ , Nam SJ , Kim SW , Yu J , Lee SK , Lee JE
Published: February 2018

Purpose

The 21 gene expression assay, Oncotype DX (ODX) is costly (the current estimated cost is ˜$4000), and were tested in only approximately one-third of breast cancer patients who meet the inclusion criteria in the United States. Recent study of University of Tennessee Medical Center reported a novel nomogram for prediction of ODX recurrence score using clinico-pathologic data, which was based on a large dataset from the National Cancer Data Base (NCDB). The purpose of this study was to confirm that the nomogram could predict ODX score group accurately with Korean data, which is different from the NCDB in terms of ethnicity.

Methods

A retrospective review was performed with 218 patients who received breast-conserving surgery or mastectomy at Samsung Medical Center and were tested with the ODX from April 2011 to January 2017. An online nomogram calculator, provided by the University of Tennessee Medical Center on their website was used in order to calculate the probability of a low-risk or a high-risk ODX score for each patient. The cut-off value for predictive accuracy of the nomogram was set same as the original study.

Results

With the cut-off value as 90% for inspection of the commercial ODX score, high-risk group showed 33.3% positive predictive value (PPV) and low-risk group showed 68.7%. With the cut-off value as 86% for TAILORx score, PPV was 66.7% for high-risk group, and 38.9% for low-risk group. The sensitivity of the nomogram for the low-risk group commercial ODX score was 96.8%, and 33.3% for the TAILORx score. For the high-risk group, sensitivity was 20% for the commercial ODX score, and 16.7% for the TAILORx score.

Conclusions

Although the nomogram for prediction of ODX score was based on a large dataset of NCDB, it could not be generalized to patients in Asia. Further studies based on large data from different ethnicities should be performed to develop the nomogram for patients worldwide.

Citation Format: Kim J-M, Ryu JM, Kim I, Choi HJ, Nam SJ, Kim SW, Yu J, Lee SK, Lee JE. The accuracy of nomograms based on large dataset using clinico-pathologic variables for prediction of oncotype DX breast cancer recurrence score [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 P5-11-01.
Abstract P5-22-21: Radioactive seed and targeted axillary dissection: A feasibility study
Authors: Boulva K , Rodriguez-Qizilbash S , Guilarte L , Lazizi S , Robidoux A , Younan R , Patocskai E
Published: February 2018

Targeted axillary dissection (TAD) with a radioactive seed is a new and promising technique to evaluate the axillary status in post-neoadjuvant chemotherapy (NACT) node-positive breast cancer patients. This study aims to evaluate the feasibility of TAD with a radioactive seed in a Canadian setting.

We conducted a retrospective observational study of a prospectively gathered database of patients having undergone TAD with a radioactive seed implanted in a proven metastatic axillary node, between 2015 and 2017 in our institution. An iodine-125 radioactive seed was implanted under ultrasound guidance by trained radiologists. Patients then underwent standard sentinel lymph node biopsy (SLNB) using technicium-99 and blue dye, as well as selective removal of the node containing the radioactive seed. Data was gathered from electronic medical records and chart review.

Nine patients with a median age of 54 underwent TAD for unilateral breast cancer post-NACT between 2015 and 2017, three of which were "triple-negative". A median of 3 lymph nodes were removed, including that which contained the radioactive seed. Postoperative pathological evaluation showed 4 patients with positive nodes and 5 pathologic complete responses in the axilla. In all patients, the seed had been accurately positioned in a positive node (no false negatives). The seed also located a positive retropectoral node that would otherwise have been missed using standard dual tracer SLNB. No complications due to the use of the radioactive seed were encountered. All implanted seeds were identified and retrieved within the pathology specimen.

In our experience, TAD with a radioactive seed combined to dual tracer SLNB is an accurate and safe method of evaluating the axillary lymph node status in post-NACT node positive breast cancer patients. Further studies with larger cohorts are warranted to ensure continued feasibility and reproducibility of our positive results.

Citation Format: Boulva K, Rodriguez-Qizilbash S, Guilarte L, Lazizi S, Robidoux A, Younan R, Patocskai E. Radioactive seed and targeted axillary dissection: A feasibility 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 P5-22-21.
Abstract P6-03-03: Not presented
Authors: Henderson MC , Silver M , Tran Q , Mulpuri R , Letsios E , Reese DE , Wolf J
Published: February 2018

This abstract was not presented at the symposium.
Abstract P6-05-02: Targeting vesicular trafficking machinery for breast cancer therapeutics
Authors: Mitra S , Vykoukal J , Jeong K , Mills G
Published: February 2018

The Rab GTPase family is a key regulator of vesicular import, transport and export. Deregulation of vesicular trafficking promotes undesirable intercellular cross talk via exosomes that contribute to cancer pathophysiology. Preclinical and clinical studies underscore a role for exosomes and their cargo in breast cancer development, progression, metastasis, and resistance to therapy. While many studies have approached the role of exosomes in cancer pathophysiology, the 'rules' governing their production and cargo sorting represents a major unexplored gap in knowledge. Exosomes arise from internal budding of specific endosomal compartments. Rab11 GTPase family members comprised of Rab11a, Rab11b and Rab25 are critical regulators of endocytic cargo trafficking specifically of apical and recycling endosomes. Previously, our lab has shown that Rab25 is amplified and contributes to oncogenesis in both ovarian and Luminal B breast cancers. However, Rab25 is lost and when re-expressed ectopically, it inhibits invasion and migration in Claudin Low tumors suggesting a cell-lineage and context dependent function. Importantly, while in Luminal B cancer, Rab25 and its downstream effector RCP (Rab coupling protein), collaborate in driving oncogenesis, in Her2+ cancers, RCP expression is protective. Further our group recently uncovered the presence of a stroma enriched “reactive protein signature” in ER+/Her- group that is indicative of good outcome for patients. Indeed, many of the “reactive signature” proteins are reported in exosomal cargo by others. Taking together, our ongoing study utilizes a panel of breast cancer cell lines representing ER+ve/Her2+; ER+/Her-, ER-/Her2+, and ER-/Her- to evaluate the role of Rab11 family in modulating vesicular trafficking that alters the exosome biology and how that may contribute to tumor- stroma communications. Our preliminary results show that indeed over expression of Rab25 differentially alters size and number of extracellular vesicles in Luminal B cancers when compared to the Claudin

Low subtype. Using a novel class of peptides that interrupt the cellular functions 25, we are investigating if Rab25 expression can be associated with an exosomal cargo profile in each subtype of breast cancer, which could then serve as a biomarker for tumor-stroma interaction.

Citation Format: Mitra S, Vykoukal J, Jeong K, Mills G. Targeting vesicular trafficking machinery for breast cancer therapeutics [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 P6-05-02.
Abstract P6-08-21: Early breast cancer-specific mortality in women with early stage breast cancer: Epidemiological and clinical characteristics
Authors: Johnson HM , Wong JH , Vohra NA , Muzaffar M
Published: February 2018

Background and Aim:

The five-year survival for women with stage I-II breast cancer is 93-100%. Despite standard of care treatment, a small subset of these women suffer early breast cancer-specific mortality and die within 12 months of diagnosis. This subset of women has not been previously described. The aim of this study is to characterize the incidence, demographics, and clinical characteristics of women with early stage breast cancer who suffer early breast cancer-specific mortality.

Methods:

Retrospective population study of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry of women diagnosed with stage I, IIA, or IIB breast cancer between 2004 and 2010. Data were filtered to histology codes 8500-8543 and 8575. Patient demographics (age, race, ethnicity) and clinical characteristics (stage, T stage, N stage, grade, ER status, PR status) of women in the early mortality subset were compared with those of women who survived > 12 months via the Chi-square test and the student t-test.

Results:

259,380 women formed the basis of our analysis. 4,572 women (0.018%) died within 12 months of diagnosis. Compared with those who survived > 12 months, women who suffered early breast cancer-specific mortality were on average older (mean age 65.7 years versus 60.3 years, p<0.00001) and more likely to be Hispanic (14.3% versus 8.9%, p<0.00001) or black (11.0% versus 9.1%, p<0.00001). Clinical characteristics associated with early mortality included higher stage (stage IIA 34.2% versus 29.4%, stage IIB 21.8% versus 12.9%, p<0.00001), higher T stage (T2 40.5% versus 28.1%, T3 3.1% versus 1.6%, p<0.00001), higher N stage (N1 29.7% versus 23.2%, N2 0.8% versus 0.4%, N3 0.4% versus 0.1%, p<0.00001), higher grade (moderate 39.3% versus 42.5%, high 40.0% versus 31.5%, p<0.00001), higher rates of ER negativity (27.2% versus 19.0%, p<0.00001), and higher rates of PR negativity (38.5% versus 30.2%, p<0.00001).

Conclusions:

Breast cancer-specific mortality within 12 months of diagnosis of stage I-II breast cancer is a rare phenomenon which has not been previously characterized. There are several demographic and clinical features associated with early mortality, however further research is needed to identify specific prognostic factors that will allow identification of women at risk for early mortality at the time of diagnosis.

Citation Format: Johnson HM, Wong JH, Vohra NA, Muzaffar M. Early breast cancer-specific mortality in women with early stage breast cancer: Epidemiological and clinical characteristics [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 P6-08-21.
Abstract P6-09-03: Gene expression patterns in younger versus older HR+ breast cancer patients: An age-related analysis of HoxB13/IL17BR (H/I), proliferation status, and quantitative hormone receptor expression
Authors: Melisko M , Chien AJ , Poage GM , Salganik M , Schnabel CA , Ruddy KJ , Blackwell K
Published: February 2018

Background: HR+ breast cancer in younger vs older patients may have distinct biological features. The Breast Cancer Index (BCI) is a gene expression-based assay that includes two component biomarkers: the HoxB13/IL17BR (H/I ratio), an endocrine response biomarker; and the molecular grade index (MGI), a set of proliferation-related genes. The objective of this study was to assess age-related associations with endocrine sensitivity (H/I), proliferative status (MGI), and quantitative expression of ER and PR.

Methods: Data were extracted from the BCI Clinical Database for Correlative Studies, an IRB-approved de-identified database containing clinicopathologic and molecular variables from clinical cases submitted for BCI testing. Molecular results from H/I, MGI, and quantitative (qPCR–based) ER and PR were analyzed across age groups. Chi-squared tests and ANOVA were used to compare the results between age groups (<40y, 40-49y, 50-59y, 60-69y, and ≥70y).

Results: Analyses included 19,126 patients (median age at diagnosis 58.6y; 4.5% <40y, 20.6% 40-49y, 28.9% 50-59y, 32.5% 60-69y, and 13.6% ≥70y). Proliferation status (MGI) was significantly higher in patients <40y and 40-49y compared to older groups (P<.0001).H/I analysis indicated a similar distribution of high versus low endocrine responsiveness across all groups (P=.94), except the 40-49y group, in which fewer patients had high H/I (44.2% in <40y, 39.4% in 40-49y, 43.7% in 50-59y, 43.7% in 60-69y, and 43.1% in ≥70y; P=.0001). Median qER increased with age (P<0.0001), while qPR was similar across all age groups except for the 40-49y group (P=.57), in which expression was higher (P<.0001).

Conclusion: Results from >19,000 patients with early-stage HR+ breast cancer and BCI testing showed a broad distribution in all variables. Tumors from the youngest patients (<40y) had the highest expression of proliferative genes and the lowest quantitative ER expression. However, endocrine response, according to the H/I biomarker, does not appear to be strongly linked to age.

Citation Format: Melisko M, Chien AJ, Poage GM, Salganik M, Schnabel CA, Ruddy KJ, Blackwell K. Gene expression patterns in younger versus older HR+ breast cancer patients: An age-related analysis of HoxB13/IL17BR (H/I), proliferation status, and quantitative hormone receptor expression [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 P6-09-03.
Abstract P6-11-13: Not presented
Authors: Kim JH , Park HS , Lim SM , Yoon KH , Kim JY , Park S , Kim SI , Cho YU
Published: February 2018

This abstract was not presented at the symposium.
Abstract P6-11-20: Not presented
Authors: Bargallo-Rocha JE , Gutierrez-Zacarias LM , Gallardo-Alvarado LN , Esparza-Arias N , Shaw-Dulin RJ , Vazquez-Romo R , Robles-Vidal CD , Cantu-De Leon DF
Published: February 2018

This abstract was not presented at the symposium.
Abstract P6-13-03: Breast cancer-specific mortality (BCSM) in patients with node-positive (N+) breast cancer (BC) treated based on the 21-gene assay in clinical practice
Authors: Shak S , McCullough D , Petkov VI
Published: February 2018

Introduction: The Recurrence Score® (RS) assay was shown in SWOG 8814 to predict chemotherapy (CT) benefit for patients (pts) with N+ BC and RS ≥31 but not RS <18. As we await the randomized RxPONDER results for RS 0-25, we characterized BCSM for RS groups (cutoffs of 11, 18, 25, and 31) in the large population-based SEER study of pts treated based on RS results.

Methods: RS results were provided electronically to SEER registries per their linkage methods (Petkov npj Breast Cancer 2016). Eligible pts were diagnosed (Jan 2004 - Dec 2012) with N+ (micrometastases, 1-3 positive nodes), HR+, HER2-negative BC, and had no prior malignancy or multiple tumors. BCSM estimates by reported CT use were computed using standard cutpoints of 18 and 31 and TAILORx/RxPONDER cutpoints of 11 and 25, and should be interpreted cautiously given known under-reporting of CT use to SEER and lack of randomization.

Results: Among 6,483 pts with RS results, 1,312 (20%) had RS <11, 2,478 (38%) had RS 11-17, 1,831 (28%) had RS 18-25, 432 (7%) had RS 26-30, and 430 (7%) had RS ≥31. There was a significant association between RS results and BCSM (p<0.001) without and with adjustment for age, tumor size, and grade. Reported CT use and 5-y BCSM increased with increasing RS result (Table). For pts with RS <11 and RS 11-17, CT use was reported in approximately a quarter of pts, and 5-y BCSM was low regardless of CT use. For pts with RS 18-25, CT use was more common and the 5-y BCSM was about 2%. For pts with RS of 26-30 or ≥31, CT was common, and higher 5-y BCSM was observed.

5-y BCSM, by RS Group and Reported CT Use CT reported as ‘No/Unknown’CT reported as ‘Yes’RS groupN (%)5-y BCSM (95% CI)N (%)5-y BCSM (95% CI)<111066 (81%)1.8% (0.7%, 4.6%)246 (19%)1.3% (0.3%, 5.3%)11-171869 (75%)0.5% (0.2%, 1.1%)609 (25%)2.3% (0.9%, 5.8%)18-251034 (56%)2.0% (1.0%, 3.9%)797 (44%)1.9% (0.8%, 4.5%)26-30144 (33%)7.7% (2.8%, 20.3%)288 (67%)4.0% (1.6%, 10.1%)≥3199 (23%)11.9% (5.3%, 25.6%)331 (77%)11.1% (6.9%, 17.6%)

Conclusion: Reported CT use and 5-y BCSM in N+ BC increased with increasing RS results in “real-world” clinical practice. 5-y BCSM with RS <18 was less than 2% in pts with no or unknown CT use. 5-y BCSM in pts treated based on RS results appears to increase considerably with RS >25.

Citation Format: Shak S, McCullough D, Petkov VI. Breast cancer-specific mortality (BCSM) in patients with node-positive (N+) breast cancer (BC) treated based on the 21-gene assay in clinical practice [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 P6-13-03.
Abstract PD6-01: Prevalence of PDL1 and tumor infiltrating lymphocytes (TILs) in primary and metastatic TNBC
Authors: Li Y , Chang C-W , Tran D , Denker M , Hegde P , Molinero L
Published: February 2018

Background: Metastatic Triple Negative Breast Cancer (TNBC) is an aggressive breast cancer subtype with a high unmet medical need and limited therapeutic options. PDL1 on immune cells (IC) and TILs were associated with activity to the anti-PDL1 mAB atezolizumab in mTNBC (Schmid AACR 2017). PDL1 IC >=1% is the diagnostic hypothesis for TNBC atezolizumab studies. The goal of the current project was to evaluate the prevalence of PDL1 and TILs in primary and metastatic TNBC samples.

Methods: FFPE tumor tissue from pathology documented TNBC tissues were centrally tested for PDL1 IHC on tumor cells (TC) and infiltrating immune cells (IC) (VENTANA SP142 assay) and quantified as percentage of tumor area. TILs were evaluated as a percentage of tumor area and PD-L1 gene (CD274) expression was quantified by Fluidigm.

Results: 669 tumors were evaluable for PD-L1 by IHC and TILs. 280 samples were annotated as primary tumors and 179 as metastases with 210 denoted as unknown. PDL1 IC and TC immunostaining was correlated to PD-L1 transcript expression (r = 0.55 and r = 0.51, respectively). 84% of samples had no tumor cells expressing PDL1 and 16% had at least 1% of PDL1 in TC. 44% of the samples had no PDL1 in the immune cells, 35% expressed PDL1 IC [31% to <5%] and 21% PDL1 IC 35%. PDL1 distribution was similar between primary and metastases, with median of 1% and 0% for PDL1 IC and TC, respectively. Analyses of anatomical locations suggest that PDL1 IC is highest in lymph nodes (median IC = 3%), lowest in liver metastases (median IC = 0.5%) while breast tissue is intermediate (median IC = 1%). The correlation between PDL1 IC and TILs is r = 0.69. TILs were numerically higher in primary compared to metastases (10% vs 5%). Anatomical TIL distribution confirmed liver metastases as least infiltrated, while breast, lymph node and lung metastases with similarly higher values (5% vs 10%, respectively). Concordance analyses in intra-individual synchronous and asynchronous matched pairs were performed at a cutoff of PDL1 IC 31%. Concordance of matched specimens was 82% in 11 synchronous pairs and 75% in 20 asynchronous pairs.

Conclusions: Prevalence of PDL1 IHC is similar between primary and metastatic TNBC samples. Although PDL1 IC and TILs are highly correlated, TILs are less prevalent in metastases compared to primary tissue. Anatomical location may influence prevalence of both PDL1 IC and TILs. Concordance of PDL1 in matched pairs is high, suggesting PDL1 IC may be a stable biomarker.

Citation Format: Li Y, Chang C-W, Tran D, Denker M, Hegde P, Molinero L. Prevalence of PDL1 and tumor infiltrating lymphocytes (TILs) in primary and metastatic TNBC [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 PD6-01.
Abstract PL2: Advances in the understanding and the applications of mutational signatures in human cells
Authors: Nik-Zainal S
Published: February 2018

A cancer genome is an historical account of the mutagenic activity that has occurred throughout the development of the tumour. Indeed, every mutation matters. While driver mutations were the main focus of cancer research for a long time, passenger mutational signatures, the imprints of DNA damage and DNA repair processes that have been operative during tumorigenesis, are also biologically informative.

We previously outlined the methods for identifying and quantifying base substitution mutational signatures present in primary human cancers. Recently, the intellectual framework of mutational signatures was extended to include six novel rearrangement signatures. Exploring this in >2,500 whole genome sequenced tumours of multiple tumour types, reveals how our early (and rather simplistic) thinking of mutational signatures, requires critical re-evaluation. There are more nuances than previously appreciated.

Diving into the detail of individual mutational signatures, we reveal intriguing mechanistic insights into the DNA damage and repair processes that mark the landscape of cancer genomes. In some instances, our findings invite more thoughtful consideration of that relatively binary distinction between drivers and passengers. Furthermore, we demonstrate why our whole genome profiling methods could assist in taking things to a clinical level, with mutational signatures forming an additional weapon in the arsenal of cancer diagnostics and therapeutic stratification, in the modern war against cancer.

Finally, we validate cancer mutational signatures using cell-based model systems and arrive at new realisations (unpublished). This powerful approach (humbles the analyst and) emphasises how biological exploration of big data still relies indispensably on experimental work to truly advance understanding.

Citation Format: Nik-Zainal S. Advances in the understanding and the applications of mutational signatures in human cells [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 PL2.
Impact of Health Authority Control Measures Aimed at Reducing the Illicit Use of Anabolic-Androgenic Steroids
Authors: Vázquez-Mourelle Raquel , Carracedo-Martinez Eduardo , Figueiras Adolfo
Published: February 2018

Objective: To evaluate two interventions on anabolic-androgenic-steroids (AAS) dispensation in retail pharmacies. Material and Methods: The study was conducted in a north-western region of Spain. Data were the AAS supplied by wholesale drug distributors to retail pharmacies over a period of 102 months. It is designed as an ecological time-series study; the dependent variables were daily defined doses per 1,000 inhabitants per day of each drug. The two interventions evaluated were: (1) an inspection program intended for those retail pharmacies where there was an irregular dispensation and (2) a regulation put forth forcing these pharmacies to carry out additional registers. The medications studied were stanozolol, nandrolone, methenolone, testosterone and mesterolone. Results: The pre-intervention use of AAS displayed a rising trend. There was an immediate reduction of 30.56% after the first intervention, and a further reduction of 35.25% after the second. There was a seasonal pattern of use in the pre-intervention period, pointing to an increased demand at the end of spring and beginning of summer. The most abused drugs were stanozolol and nandrolone. Conclusion: The health actions were very effective, in that they brought about a sharp reduction in the illicit use of AAS. These interventions could be applied to other drugs in which abuse were detected.
Intrathecal Administration of CXCL1 Enhances Potassium Currents in Microglial Cells
Authors: Deftu Alexandru-Florian , Ristoiu Violeta , Suter Marc Rene
Published: February 2018

The functioning of microglial cells inside the central nervous system depends on their ion channels expression. Microglia are capable of synthesizing different cytokines and chemokines, including CXCL1, and responding to their action via specific receptors. In this study, we explore the effect of intrathecal injection of CXCL1 on potassium currents, expressed in CX3CR1-Green Fluorescent Protein labeled microglia in transgenic mice. The results showed that CXCL1 hyperpolarized the cells by enhancing inward rectifying potassium currents and increasing the membrane area, suggesting an activating effect on microglia.
Does Endothelin-1 Raise or Lower Blood Pressure in Humans?
Authors: Schiffrin Ernesto L.
Published: February 2018

Subject of Review: Gupta et al. [Cell 2017; 170: 522–533] have shown that a genetic variant associated with the 5 vascular diseases is a distal regulator of endothelin (ET)-1 gene (EDN1) expression. A common single nucleotide polymorphism (SNP) in the third intron of the PHACTR1 gene, rs9349379, is the potential variant responsible for increased risk of coronary artery disease, and lower risk of migraine, carotid dissection, fibromuscular dysplasia, and hypertension. Since ET-1 acts through ET type B receptors (ETBR) on endothelial cells to stimulate the production of nitric oxide and prostacyclin and induce vasodilation, this may contribute to these findings. Second Opinion: However, ET-1 has been demonstrated to play a role in experimental and human hypertension. How can enhanced transcription of EDN1 and translation leading to increased production of ET-1 by endothelial cells play a role in hypertension despite the availability of data that suggest a hypotensive action of ET-1? This could depend on the genetic background of individuals. In some humans, the increased ET-1 vasoconstrictor action on ETAR and ETBR in vascular smooth muscle might predominate over the vasodilator effects exerted via endothelial ETBR, thus resulting in elevated blood pressure. Conclusion: Alternatively, hypertension could be attributed to renal actions of ET-1. Either of these pathophysiological actions may explain a hypertensive role of ET-1 despite a lower risk of hypertension associated with the G allele at rs9349379, the common SNP in the PHACTR1 gene that is a distal regulator of EDN1 and leads to an increased expression of ET-1.
Functions and Roles of Long-Non-Coding RNAs in Human Nasopharyngeal Carcinoma
Authors: Wu JingJing , Hann Swei Sunny
Published: February 2018

Nasopharyngeal carcinoma (NPC) is one of the most common cancers originating in the nasopharynx and occurring at high frequency in South-eastern Asia and North Africa. Long non-coding RNAs (lncRNAs) are a class of non-protein-coding RNA molecules and key regulators of developmental, physiological, and pathological processes in humans. Emerging studies have shown that lncRNAs play critical roles in tumorgenicity and cancer prognosis. With the development of deep sequencing analyses, an extensive amount of functional lncRNAs have been discovered in nasopharyngeal carcinoma tissues and cell lines. However, the roles and mechanisms of aberrantly expressed lncRNAs in the pathogenesis of NPC are not fully understood. In this review, we briefly illustrate the concept, identification, functional characterization, and summarize recent advancements of biological functions of lncRNAs with heterogeneous mechanistic characterization and their involvement in NPC. Then, we describe individual lncRNAs that have been associated with tumorgenesis, growth, invasion, cancer stem cell differentiation, metastasis, drug resistance and discuss the strategies of their therapeutic manipulation in NPC. We also review the emerging insights into the role of lncRNAs and their potential as biomarkers and therapeutic targets for novel treatment paradigms. Finally, we highlight the up-to-date of clinical information involving lncRNAs and future directions in the linking lncRNAs to potential gene therapies, and how modifications of lncRNAs can be exploited for prevention and treatment of NPC.