bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P2-01-04: Use of axillary ultrasound impacts outcome of node positive breast cancer patients
Authors: Verheuvel NC , Voogd AC , Tjan-Heijnen VCG , Roumen RMH
Published: May 2019

Background The Z0011 trial initiated a paradigm shift in the treatment of axillary node positive breast cancer patients. Treatment strategy, however, starts with the information gathered by the diagnostic axillary work up. This can either be done by sentinel lymph node biopsy (SLNB) or ultrasound guided lymph node biopsy (UGLNB). We examined whether there are relevant clinical and prognostic differences between patients found node positive by these two diagnostic selection processes.

Methods Patients diagnosed with invasive breast cancer in the Netherlands between January 2000 and December 2013 were studied. Patients with no clinically palpable lymphadenopathy (cN0) and node-positive disease after an axillary lymph node dissection (ALND) were included. Patients with stage IV breast cancer, with clinical stage T3-T4 breast tumor according to the TNM-classification, those treated within the neo-adjuvant setting, patients with palpable axillary nodes (cN≥1) and patients who did not undergo an ALND were excluded.

Results A total of 14,730 patients fulfilled the inclusion criteria, of whom 9,448 were included in the SLNB group and 5,282 in the UGLNB group. Patients in the UGLNB group were older at diagnosis (p<0.001), had larger tumors (p<0.001), a higher tumor grade (p=0.001), and were more likely to have a negative hormonal receptor status (p<0.001) and to undergo a mastectomy (p<0.001). Patients in the UGLNB group were also more likely to have ≥3 positive axillary lymph nodes (p<0.001) and, after adjustment for these differences, had a worseoverall survival (HR=1.64; 95% CI=1.53-1.75) compared to the node-positive patients in the SLNB group.

Conclusion Our multicenter study shows that patients with a positive UGLNB have less favorable disease characteristics and a worse prognosis compared to patients with a positive SLNB. The diagnostic selection process plays an important role when axillary treatment strategies are considered. Therefore, we conclude that the conclusions of the Z0011 trial cannot (yet) be applied to patients with a positive UGLNB.

Citation Format: Verheuvel NC, Voogd AC, Tjan-Heijnen VCG, Roumen RMH. Use of axillary ultrasound impacts outcome of node positive 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 P2-01-04.
Abstract P2-05-28: BCL2 is a prognostic marker for subtype specific breast cancer
Authors: Kim HS , Eom YH , Song BJ , Chae BJ
Published: May 2019

This abstract was withdrawn by the authors.
Abstract P2-07-08: Neuroleptics in breast cancer risk
Authors: Johnston A , Garcia S , Hein S , Bu W , Yi L
Published: May 2019

This abstract was not presented at the symposium.
Abstract P3-13-13: Breast-conserving surgery plus hormone therapy without irradiation in elderly women with early breast cancer
Authors: Inoue H , Hirano A , Ogura K , Hattori A , Yukawa H , Sakaguchi S , Matsuoka A , Tanaka N , Kodera A , Kamimura M , Fujibayashi M , Naritaka Y , Shimizu T
Published: May 2019

Background

The meta-analysis of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) revealed that whole-breast irradiation after breast conserving surgery (BCS) decreased ipsilateral breast tumor recurrence (IBTR) and breast cancer-related death. However, elderly patients can find daily hospital attendance difficult, and their IBTR risk is low. A randomized control trial was performed in women aged ≥70 years with hormone-positive breast cancer to investigate the usefulness of breast-conserving therapy without irradiation (Hughes et al. N Engl J Med 2004). Since September 2001, we have offered BCS plus hormone therapy without irradiation in patients who satisfy the following criteria: age ≥60 years; pathologically node negative, hormone-positive breast cancer; a negative surgical margin; and no lymphovascular invasion. We assessed prognosis in patients who chose this option.

Patients and methods

Between September 2001 and December 2014, 219 patients met the inclusion criteria; 90 and 129 patients underwent BCS plus hormone therapy with or without irradiation, respectively. The cumulative IBTR incidence and overall survival (OS) for the groups was evaluated. A negative surgical margin was defined as a margin of ≥5 mm.

Results

The median ages at operation were 73 years (range, 60–88 years) and 65 years (range, 60–80 years) for the without and with irradiation groups, respectively (p <0.001). There were no significant differences in tumor size, lymph node metastasis, or adjuvant therapy between the groups. The median follow-up duration is presently 4.6 years. IBTR was observed in 5 (3.9%) and 1 (1.1%) patient(s) in the without and with irradiation groups, respectively (p = 0.192). The 5-year IBTR cumulative incidences were 0.9% and 2.2%, and the 10-year were 6.7% and 2.2%, for the without and with irradiation groups, respectively (p = 0.390). The 5-year OS rates were 93.8% and 98.5%, and the 10-year OS rates were 89.7% and 94.0 for the without and with irradiation groups, respectively (p = 0.205).

Conclusion

BCS plus hormone therapy without irradiation in elderly patients is an appropriate option.

Citation Format: Inoue H, Hirano A, Ogura K, Hattori A, Yukawa H, Sakaguchi S, Matsuoka A, Tanaka N, Kodera A, Kamimura M, Fujibayashi M, Naritaka Y, Shimizu T. Breast-conserving surgery plus hormone therapy without irradiation in elderly women with early 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 P3-13-13.
Abstract P3-14-14: Endoscopic 3D latissimus dorsi muscle harvesting for immediate breast reconstruction. Results of our 7 patients experience in Antoine Lacassagne Nice Cancer Center
Authors: Barranger E , Dejode M
Published: May 2019

Introduction :

The harvest of the latissimus dorsi muscle for the realization of immediate breast reconstruction induces a large dorsal scar measuring up to 20 centimeters, while only the muscle is used. We present here the results of our experience of endoscopic harvesting of the latissimus dorsi muscle using 3D technology. Our main objective is to reduce the dorsal scar and second assess the functional consequences for patients.

Methods:

Between December 1st, 2015 , and June 1st, 2016, there were 7 patients who underwent latissimus dorsi endoscopic harvesting, with 3D technology, for an immediate breast reconstruction after a skin-sparing or nipple sparing mastectomy.

Results:

4 patients had latissimus dorsi muscle with breast implant and 3 patients by latissimus dorsi muscle only. The age average was 55 years (range 45-70). The mean length of surgery was 250 minutes (range 150- 380). The mean length of hospitalization was 7 days (range 4-12 days). One patient treated for local recurrence had skin necrosis because of previous radiotherapy. Donor site seroma was the main post surgery drawback. Patients on average benefited from 3 evacuations (range 1-5) of 850ml (range 640-1270ml). Acceptance of the reconstructed breast was good in six cases, and poor in one case. Only one patient reported discomfort at the donor site 1 month after surgery.

Conclusion:

The endoscopic 3D latissimus dorsi flap harvesting allows to reduce donor site scar. There is no significant difference concerning complications or post-operative pain and functional discomfort between the endoscopic and classic harvesting procedure.

Citation Format: Barranger E, Dejode M. Endoscopic 3D latissimus dorsi muscle harvesting for immediate breast reconstruction. Results of our 7 patients experience in Antoine Lacassagne Nice Cancer Center [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 P3-14-14.
Abstract P4-15-02: Investigating the use estrogen receptor β agonists in the prevention of breast cancer using a transgenic mouse model
Authors: Samayoa C , Krishnegowda NK , Vadlamudi RK , Tekmal RR
Published: May 2019

Breast cancer is the most common cancer among women worldwide. In the United States, 1 in 8 women will develop breast cancer during her lifetime, and in 2016 over 240,000 new cases will be diagnosed. Incidence rates differ by geographic location, with women living in Asia having the lowest rates. However, after migrating to the U.S and adopting a western diet their rates increase. This highlights the importance of lifestyle, including diet, in modulating breast cancer risk. Soy has been previously implicated as the dietary component contributing to the reduced breast cancer rates in Asian women. Compounds that can selectively activate Estrogen Receptor β have been identified in plants, including soy. Given the tumor-suppressive properties of ERβ, it may be possible to use these agonists in the chemoprevention of breast cancer.

The objective of this study was to investigate the utility of using ERβ agonists in the prevention of breast cancer using a transgenic mouse model. MMTV-HER2/neu mice develop premalignant lesions at 4-5 months, and tumors starting at month 7 due to overexpression of the Her2/neu proto-oncogene. MMTV-HER2/neu mice were treated with 2 different ERβ agonists, S-equol or LY500307, for 3 months and evaluated for branching, hyperplasia and differential gene expression. When compared to controls, ERβ agonist-treated mice exhibited a significant decrease in branching and ductal hyperplasia, with no change in body weight. Differential gene expression analysis revealed 218 modified genes in response to S-equol treatment, and 258 genes modified by LY500307 treatment, with an overlap of 36 genes. Pathway analysis identified an enrichment for chemokines signaling pathways, particularly TNF, in the reversal of hyperbranching resulting from treatment with ERβ agonists.

Although previous studies have demonstrated crosstalk between ER's non-genomic signaling and growth factor signal transductions pathway, this is the first study to demonstrate the impact of ERβ activation on HER2/neu mediated pre-neoplastic changes. Our study suggest that ER β agonist treatment may be a valuable therapeutic option for the chemoprevention of breast cancer in women at increased risk.

Citation Format: Samayoa C, Krishnegowda NK, Vadlamudi RK, Tekmal RR. Investigating the use estrogen receptor β agonists in the prevention of breast cancer using a transgenic mouse model [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 P4-15-02.
Abstract P6-01-04: Evolutionary analyses of matched primary and metastatic breast cancer reveal both linear and parallel progression with lack of axillary lymph node involvement
Authors: Ullah I , Muralidharan KG , Alkodsi A , Kjällquist U , Stålhammar G , Lövrot J , Martinez NF , Lagergren J , Hautaniemi S , Hartman J , Bergh J
Published: May 2019

This abstract was withdrawn by the authors.
Abstract P6-01-21: Novel CD146-downstream signaling pathway involved in breast tumor suppression
Authors: Ouhtit A , Fernando A , Abd Elmageed Z , Rahman M , Zayed H
Published: May 2019

This abstract was not presented at the symposium.
Abstract P6-08-09: Cancer stem cells define 3D clonogenic growth response to rational combinations of PI3K-isoform specific inhibitors in TNBC
Authors: Carlson JH , De P , Williams C , Dey N , Leyland-Jones B
Published: May 2019

This abstract was not presented at the symposium.
Abstract BL1: Modeling Immune Response: Lessons Learned from Mouse Models of Cancer Development
Authors: Coussens L
Published: May 2019

The concept that leukocytes are critical components of solid tumors is now generally accepted, however, their role(s) in regulating aspects of cancer progression, and/or response to cytotoxic, targeted and/or immune therapy is only beginning to be understood. Utilizing de novo mouse models of mammary tumor development, we now appreciate that CD4+ T lymphocytes differentially regulate myeloid cell recruitment, activation and effector function, and in turn, activated tumor-infiltrating myeloid cells foster malignancy and repress anti-tumor immunity by a diversity of mechanisms. Treatment of tumor-bearing mice with therapeutic agents disrupting lymphocyte-myeloid interactions, myeloid activation, or myeloid functionality generally slow primary tumor growth kinetics when combined with cytotoxic therapy; however, their impact on metastases is variable. Similar to organ-specific regulatory programs co-opted to foster primary tumor growth, regulation of metastatic seeding and outgrowth is also regulated by tissue- and organ-specific mechanisms. Based on this, it stands to reason that therapeutic strategies may not be efficacious in both primary and metastatic locations. To be presented will be our recent insights into organ-specific regulation of primary and metastatic mammary cancer development by adaptive and innate immune cells regulating pro- and/or anti-tumor immunity, and new studies evaluating how attenuating protumor properties of select lymphoid and myeloid cells can be exploited to enhance therapeutic responses to cytotoxic and immune-based therapy.

LMC acknowledges generous support from the NIH / NCI, the Department of Defense Breast Cancer Research Program Era of Hope Scholar Expansion Award, Susan G. Komen Foundation, the Breast Cancer Research Foundation, the Brenden-Colson Center for Pancreatic Health, and a Stand Up To Cancer – Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant.

Citation Format: Coussens L. Modeling Immune Response: Lessons Learned from Mouse Models of Cancer Development [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr BL1.
Abstract BS1-3: New insights into early-stage bone colonization of disseminated breast cancer cells
Authors: Zhang X
Published: May 2019

The fate of disseminated tumor cells is heavily influenced by their microenvironment niche. The osteogenic niche promotes cancer cell proliferation and bone metastasis progression. We investigated the underlying mechanisms using a variety of pre-clinical models and bioinformatics analyses of clinical data. We find that disseminated tumor cells may follow a “migration-by-tethering” mechanism to reach the osteogenic niche and establish tight direct interaction with the osteogenic cells. This interaction in turn profoundly alters signaling cascades in bone micrometastases. Heterotypic adherens junctions between cancer cells and osteogenic cells induce activation of the mTOR signaling. Gap junctions mediate calcium flux from osteogenic cells to cancer cells, and activate the calcium signaling. Upon the development of these junctions, ER signaling in ER+ breast cancer cells is dramatically suppressed, conferring endocrine independence. These alterations lead to unexpected therapeutic resistance and sensitivity, which were elucidated in part by a novel ex vivo bone-in-culture array system. Our findings, together with others in the literature, demonstrate the importance of considering microenvironment effects in metastatic therapies, and suggest novel therapeutic strategies to eliminate micrometastases.

Citation Format: Zhang X. New insights into early-stage bone colonization of disseminated breast cancer cells [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr BS1-3.
Abstract ES1-3: Advanced HER2-positive breast cancer: Overcoming treatment resistance
Authors: Rimawi M
Published: May 2019

For two decades, HER2 has been an attractive therapeutic target. Anti-HER2 agents have transformed the care of HER2+ breast cancer and greatly improved its outcomes. However, treatment resistance remains a considerable clinical problem, and some patients still recur and progress despite optimal treatment. A particular challenge in advanced HER2+ breast cancer remains to be CNS metastasis. Special attention needs to be given to this devastating event given its serious sequelae, and its prevalence among patients battling this disease. As more agents are being approved in the early setting, improving outcomes in this setting, patients who suffer a recurrence may have more limited options and more resistant disease.

The good news is that there is a number of anti-HER2 agents being explore in the advanced setting of HER2+ breast cancer. They fit into three major categories: new or optimized monoclonal antibodies, antibody-drug conjugates, and tyrosine kinase inhibitors. There is also great interest in studying other classes of agents in combination with anti-HER2 treatment, like immune-oncology agents, in this space.

The plethora of agents being developed in this setting highlights the importance to understand more about potential mechanisms of resistance. This will help guide development strategies, deliver tailored treatment approaches, and design more effective agents and regimen.

Resistance may be the end result of many possible molecular changes that mediate its emergence, and a variety of strategies are needed to elucidate them. That includes comprehensive in depth molecular profiling, as well as functional validation of detected alterations. Moreover, each tumor may have many underlying molecular changes in different cell sub-populations.

It is therefore mandatory that development strategies for new agents and combinations should rely on clinical and biologic factors to help improve outcomes for patients with advanced HER2+ breast cancer.

Citation Format: Rimawi M. Advanced HER2-positive breast cancer: Overcoming treatment resistance [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES1-3.
Abstract ES10-2: Mining noncoding mutations for drivers of development in ER alpha-positive breast cancer
Authors: Lupien M
Published: May 2019

Large-scale analysis of whole genome sequencing of breast tumors has identified thousands of genetic alterations, such as single-nucleotide variants (SNVs), outside of gene coding sequences. Delineating the functional impact of these noncoding SNVs is challenging, limiting their inclusion in precision genomics medicine pipelines. Pan-cancer attempts to detect evidence for positive selection within individual CREs identified promoters of a limited number of genes such as TERT. By considering the enrichment of noncoding mutations in cistromes as opposed to individual CREs, we identify the enrichment of noncoding SNVs in cistromes of breast cancer driver transcription factors, including FOXA1. This parallels enrichment of breast cancer genetic predispositions over these transcription factor cistromes. Furthermore, somatic SNVs accumulate in the regulatory plexus of some of these driver transcription factors providing evidence for a multi-targeted approach to disrupt their activity in breast cancer. In conclusion, our results support a functional impact of somatic SNVs converging on the cistrome of driver transcription factors in breast cancer. Altogether, we show how to interrogate noncoding SNVs to delineate the oncogenic determinants of breast cancer to be considered for therapeutic intervention.

Citation Format: Lupien M. Mining noncoding mutations for drivers of development in ER alpha-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES10-2.
Abstract ES10-3: Blockade of estrogen signaling boosts antitumor immunity by inhibiting tumor-induced pathological myelopoiesis
Authors: Conejo-Garcia J
Published: May 2019

Although the role of estrogen signaling in the progression of a subset of breast tumors has been underscored by the clinical use of Estrogen Receptor antagonists, how estrogens impact protective anti-tumor immunity remains poorly investigated. Here we show that estrogen signaling accelerates the progression of different estrogen insensitive tumor models by contributing to tumor-promoting emergency myelopoiesis. This results in increased mobilization of myeloid-derived suppressor cells (MDSCs), and also increases their intrinsic immunosuppressive activity on a per cell basis, in vivo in the bone marrow of tumor-bearing hosts. Accordingly, estrogens have a profound effect on T-cell-dependent anti-tumor immunity and tumor-promoting inflammation, even independently of the sensitivity of tumor cells to estrogen signaling. Differences in tumor growth in the presence of estrogen-insensitive tumor cells are dependent on blunted anti-tumor immunity and, correspondingly, disappear in immunodeficient hosts and also upon MDSC depletion. Mechanistically, estrogen receptor alpha activates the STAT3 pathway in human and mouse bone marrow myeloid precursors by enhancing JAK2 and SRC activity. Consequently, selective antagonists of estrogen receptor alpha (but not estrogen receptor beta) could have significant effects in delaying the progression of estrogen-sensitive and estrogen-insensitive tumors, providing a rationale for blocking estrogen signals to boost the effectiveness of anti-cancer immunotherapies. Our data therefore provide novel mechanistic insight into how enhanced estrogenic activity contributes to malignant progression in established tumors by driving pathological, tumor-promoting myelopoiesis. Our work suggests that new anti-estrogen drugs without agonistic effects (different from tamoxifen) could have benefits to boost protective immunity in a wide range of cancers, while augmented estrogenic activity could contribute to tumor initiation and/or malignant progression.

Citation Format: Conejo-Garcia J. Blockade of estrogen signaling boosts antitumor immunity by inhibiting tumor-induced pathological myelopoiesis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES10-3.
Abstract OT3-02-05: CORALLEEN: A phase 2 clinical trial of chemotherapy or letrozole plus ribociclib as neoadjuvant treatment for postmenopausal patients with luminal B/HER2-negative breast cancer
Authors: Gavila J , Saura C , Oliveira M , Ciruelos E , Gonzalez X , de la Peña L , Bermejo de las Heras B , Muñoz M , Fernandez P , Villagrasa P , Ortega V , Lopez R , Celiz P , Pascual T , Prat A
Published: May 2019

Background: Dysregulation of cyclin D-CDK4/6-Rb pathway is associated with endocrine resistance in hormone receptor–positive (HR+) breast cancer. Recently, a CDK4/6 inhibitor has shown unprecedented efficacy in metastatic disease, leading to its regulatory approval. Several others are currently in clinical development for the management of HR+ breast cancer in the early and advanced settings. However, it is vital to gain insights into the molecular and biological effects of this class of agents and could identify patients who can benefit the most, delaying or avoiding the use of chemotherapy.The neoadjuvant setting provides an ideal scenario to carry out these investigations. Hence, we propose to conduct an exploratory study to evaluate the biological effects and the efficacy of ribociclib in patients with primary luminal B tumors. We hypothesize that the combination of ribociclib plus letrozole may offer clinical benefit in the preoperative setting. Methods: This is a parallel, multicenter, two-arm, randomized exploratory study in postmenopausal women with primary operable HR+/HER2-negative Luminal B breast cancer designed to evaluate the clinical benefit of ribociclib plus letrozole. Eligibility includes stage I-III operable breast cancer, Luminal B by PAM50, ECOG 0-1. They will be randomized 1:1 to receive either six 28-days cycles of ribociclib (600mg; 3-weeks-on/1-week-off) plus daily letrozole (2.5mg) or chemotherapy: four cycles of AC (doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2 every 21 days) followed by weekly paclitaxel during 12 weeks. Baseline, Day 15 on-treatment, and surgical specimens will be collected for molecular characterization and evaluation of response (decrease in Ki67, change to ROR low disease) The primary endpoint is the rate of Residual Cancer Burden (RCB) per MD Anderson Cancer Center procedures. A rate of RCB 0 and 1 score at surgery, with a rank between 20% to 25% with 47 evaluable patients by group of treatment will offer a precision between 11.5% and 12.4%, respectively (95%CI). Ninety-four patients will be enrolled in 21 sites across Spain. The trial was activated in July 2017. As of June 2018, 78 patients have been recruited.

Citation Format: Gavila J, Saura C, Oliveira M, Ciruelos E, Gonzalez X, de la Peña L, Bermejo de las Heras B, Muñoz M, Fernandez P, Villagrasa P, Ortega V, Lopez R, Celiz P, Pascual T, Prat A. CORALLEEN: A phase 2 clinical trial of chemotherapy or letrozole plus ribociclib as neoadjuvant treatment for postmenopausal patients with luminal B/HER2-negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-05.
Abstract OT3-08-01: A phase Ib/II clinical trial investigating the efficacy of nitric oxide deprivation and docetaxel in triple negative breast cancer
Authors: Chung AW , Ensor JE , Darcourt J , Belcheva A , Patel T , Chang JC , Niravath PA
Published: May 2019

Triple negative breast cancer (TNBC) is an aggressive disease that currently lacks an efficacious form of therapy. Although chemotherapy is the current standard of care for metastatic TNBC, the 5-year prognosis remains grim with a high rate of disease recurrence. Cancer relapse is thought to be initiated by chemotherapy-resistant breast cancer stem cells (BCSCs). These BCSCs give rise to a diverse clonal population that results in a heterogeneous cancer, which complicates targeted therapeutic strategies. Our previous studies revealed that BCSCs utilize inducible nitric oxide synthase (iNOS)-derived nitric oxide to promote their proliferation, migration, and self-renewal capacity. In an effort to target the BCSC population, we found that iNOS inhibition with NG-monomethyl-L-arginine (L-NMMA) sensitized BCSCs to docetaxel in vivo in TNBC xenograft models, leading to decreased BCSC viability and tumor burden. These findings suggest that BCSC resist conventional therapy in a nitric oxide-dependent manner and that combination of L-NMMA with docetaxel will effectively target BCSCs to prevent further relapse. A phase Ib/II clinical trial was conducted to determine the maximum tolerated dose, recommended phase 2 dose (R2PD), dose-limiting toxicities (DLTs), and efficacy of the L-NMMA and docetaxel combination in TNBC patients with chemotherapy-refractory locally advanced or metastatic disease. For the phase Ib portion of the study, a standard Bayesian continual reassessment method is being used to investigate 7 dose levels of L-NMMA (5, 7.5, 10, 12.5, 15, 17.5, and 20 mg/kg) and two dose levels of docetaxel (75 and 100 mg/m2). Sixteen patients have been recruited to date, and based on current pharmacokinetics, pharmacodynamics, and safety data, the RP2D is expected to be docetaxel 100 mg/m2 (Day 1) and L-NMMA 20 mg/kg (Days 1-5) every 3 weeks. Two and three patients received 15 mg/kg L-NMMA + 75 mg/m2 docetaxel and 17.5 mg/kg L-NMMA + 100 mg/m2 docetaxel, respectively. Of these 5 patients, one partial responder completed 8 cycles before discontinuing treatment due to taxane-associated neuropathy. Among the five patients treated at the RP2D, only one taxane-associated DLT occurred. The overall response rate for patients treated at the higher doses was 22.2%. Early results of the phase Ib/II trial indicate the safety, tolerability, and promising activity of the first-in-class pan-NOS inhibitor L-NMMA in combination with chemotherapy in the treatment of chemotherapy-refractory TNBC.

Citation Format: Chung AW, Ensor JE, Darcourt J, Belcheva A, Patel T, Chang JC, Niravath PA. A phase Ib/II clinical trial investigating the efficacy of nitric oxide deprivation and docetaxel in triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-08-01.
Abstract P1-06-11: Microsatellite instability in triple negative breast cancers
Authors: Kurata K , Kubo M , Mori H , Kawaji H , Motoyama Y , Kuroki L , Yamada M , Kaneshiro K , Kai M , Nakamura M
Published: May 2019

Background:Microsatellite instability (MSI) is a phenotype resulting from defect in mismatch repair genes. The Food and Drug Administration approved anti-programmed death 1 (PD-1) immune checkpoint inhibitor for any solid tumor with MSI-high (MSI-H). Some tumors had good response to PD-1 blockade and it is a promising treatment for a part of refractory breast cancers. Our goal was to determine the frequency of MSI in triple negative breast cancer (TNBC), one of the most clinically aggressive subtypes.

Patients and Methods:This study included 228 patients with primary TNBC underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. Genomic DNA was extracted from formalin-fixed and paraffin-embedded tissue. Tumor and control DNA were amplified by polymerase chain reaction at the following 5 microsatellite markers: NR-21, BAT-26, BAT-25, NR-24, MONO-27. We classified the tumors as microsatellite stable(MSS), MSI-low or MSI-H.

Results: The mean age of patients was 59 years (range: 30-89) and all were women. T1 tumors were 57.9% and N0 were 67.5%. Meanwhile, the tumors with nuclear grade 3 were 66.2% and high Ki-67 (> 30%) were 66.7%. Among the 228 tumors, 222 tumors (97.4%) revealed MSS, of which 6 (2.6%) revealed MSI and 2 (0.9%) were MSI-H. Among the MSI tumors, T and N factor were showed as follows: T1: 2 tumors, T2: 3 tumors, T3: 1 tumor, N0: 5 tumors and N1: 1 tumor. Of two MSI-H tumors, one showed T1N0 and another showed T2N0. The both of them showed nuclear grade 3, high Ki-67 (> 30%) and had common following instable markers: NR-21, BAT-26 and BAT-25.

Conclusions: Our results demonstrated that the frequency of MSI-H was 0.9% (2/228). MSI might not be useful as a biomarker for immune check point inhibitors. MSI should be combined with another biomarker such as tumor mutational burden in TNBC.

Citation Format: Kurata K, Kubo M, Mori H, Kawaji H, Motoyama Y, Kuroki L, Yamada M, Kaneshiro K, Kai M, Nakamura M. Microsatellite instability in triple negative breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-06-11.
Abstract P1-07-02: Withdrawn
Authors: Di Nicola M , Volpari T , Fucà G , Romero Cordoba S , De Santis F , Rondinone O , Faraci S , Ferris F , Puricelli C , Castagnoli L , Marullo R , Cerchietti L , Pupa S
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Di Nicola M, Volpari T, Fucà G, Romero Cordoba S, De Santis F, Rondinone O, Faraci S, Ferris F, Puricelli C, Castagnoli L, Marullo R, Cerchietti L, Pupa S. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-07-02.
Abstract P1-08-19: 10-year conditional recurrence risks, overall and relative survival for breast cancer patients in the Netherlands: Taking account of event-free years
Authors: van Maaren MC , Strobbe LJ , Smidt ML , Moossdorff M , Poortmans PM , Siesling S
Published: May 2019

Background

Survival estimates valid at the time of diagnosis are of limited value for (ex-)breast cancer patients who survived several years, as it includes information on already deceased patients. This study analyzed the 10-year conditional risk of recurrent breast cancer in specific prognostic subgroups according to T and N stage and breast cancer subtypes. Secondly, we investigated 10-year conditional overall (OS) and relative survival (RS), adjusted for confounding.

Patients and methods

We selected all women diagnosed in 2005 with operated T1-2N0-1 breast cancer from the Netherlands Cancer Registry. Patients were classified into T1N0, T1N1, T2N0 and T2N1 stage. Ten-year conditional recurrence rates were calculated for every year from diagnosis for patients without an event (local (LR), regional recurrence (RR), distant metastasis (DM) or death). Ten-year conditional OS was calculated using multivariable Cox regression. RS was estimated by dividing patient survival rates by those of the general Dutch population.

Results

We included 7,969 patients: 52.3% had T1N0, 15.3% T1N1, 19.9% T2N0 and 12.5% T2N1 stage. For T1N0, 10-year LR rates changed from 4.6% at diagnosis to 0.5% in year 10. RR rates decreased from 2.3% to 0.2% and DM rates decreased from 7.8% to 0.6%. For T2N1 stage, the LR, RR and DM rates decreased from 6.2% to 0.8%, 5.2% to 0.4% and 19.6% to 1.5%, respectively. Of all patients, 1,702 patients (21.4%) had an unknown breast cancer subtype and were consequently excluded from the analyses according to subtype. Of the remaining 6,267 patients, 3,774 (60.2%) had luminal A, 1,465 (23.4%) had luminal B, 314 (5.0%) had HER2 positive and 714 (11.4%) had triple negative disease For the luminal A subtype, LR, RR and DM rates ranged from 3.9% to 0.4%, 1.7% to 0.5% and 7.3% to 1.1%, while for triple negative these rates ranged between 5.6% to 0.7%, 4.9% to 0.2% and 16.7% to 0%, respectively. Differences between subgroups attenuated over time and all recurrence rates became ≤1.5% in year 10. Ten-year OS and RS, adjusted for confounding, showed diminishing risk differences between subgroups over time.

Conclusion

Differences in recurrence rates, OS and RS between prognostic subgroups decreased as years passed by. These results highlight the importance of taking into account disease-free years to more accurately predict (ex-)breast cancer patients' prognosis over time.

Citation Format: van Maaren MC, Strobbe LJ, Smidt ML, Moossdorff M, Poortmans PM, Siesling S. 10-year conditional recurrence risks, overall and relative survival for breast cancer patients in the Netherlands: Taking account of event-free years [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-19.
Abstract P1-08-21: Association of depression and anxiety disorder with the risk of mortality in breast cancer: A national health insurance service study in South Korea
Authors: Kim YS , Shim E-J , Lee JW , Cho J , Jung HK , Kim NH , Lee JE , Min J , Noh WC , Park S-H
Published: May 2019

PURPOSE: To examine whether depression, anxiety disorder and their co-occurrence would increase the risk of mortality in patients with breast cancer, and whether antidepressant treatment would reduce the same.

PATIENTS AND METHODS: Data were retrieved from the database of the Korean National Health Insurance Service. Of 145,251 patients diagnosed with breast cancer between 2007 and 2014, 20,870 patients diagnosed with depression or anxiety disorder one year before breast cancer diagnosis were excluded. Thus, data of 124,381 patients were included in this study.

RESULTS: Anxiety disorder was more prevalent than depression in patients with breast cancer, and similar factors were associated with both depression and anxiety disorder. Overall, female sex, older age, residence in metropolitan areas, lower income, higher comorbidity, carcinoma in situ, and the receipt of any type of cancer therapies were associated with an increased risk of depression or anxiety disorder. Depression and anxiety disorder were associated with an increased risk of mortality (Hazard Ratio (HR) = 1.26, 95% CI=1.18–1.36; HR=1.14, 95% CI=1.08–1.22, respectively) and their co-occurrence further increased the risk (HR=1.38, 95% CI=1.24–1.54). Antidepressant treatment was related to a reduced risk of mortality. Compared to patients with no depression, among those with depression, the risk of mortality was 2.18 times higher (95% CI=1.69–2.81) in patients who did not receive antidepressant treatment and 1.25 times higher (95% CI =1.17–1.32) in those who received antidepressant treatment.

CONCLUSION: The current findings suggest that psychiatric comorbidities are markers of increased mortality risk in patients with breast cancer. This underscores the need for screening and treating depression and anxiety disorders to improve survival in breast cancer.

Citation Format: Kim YS, Shim E-J, Lee JW, Cho J, Jung HK, Kim NH, Lee JE, Min J, Noh WC, Park S-H. Association of depression and anxiety disorder with the risk of mortality in breast cancer: A national health insurance service study in South Korea [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-21.
Abstract P1-09-08: Hormonal factors associated with elevation of DNA methylation age in breast tissue of healthy women
Authors: Sehl ME , Henry JE , Storniolo AM , Horvath S , Ganz PA
Published: May 2019

Background: Healthy breast tissue appears older than matched peripheral blood, when using a biologic aging measurement based on DNA methylation markers. The underlying cause of this acceleration is not known. We hypothesize that cumulative estrogen exposure is associated with accelerated breast epigenetic aging. In this study, we examined factors associated with breast epigenetic age in a healthy population of women.

Methods: We used breast tissue samples from 232 healthy women donors (119 pre-menopausal, 113 post-menopausal) to the Komen Tissue Bank, with data available on variables related to cumulative estrogen exposure, including age at menarche, gravidity, parity, and menopausal status. DNA methylation experiments were performed using the Illumina EPIC 850K array platform. DNA methylation age (DNAm age) was calculated using the epigenetic clock methods developed by Horvath (2013). Total years of estrogen exposure was calculated as the difference between age at menopause (or current age) - number of live births x 9 months – number of miscarriages x 3 months. Nonparametric group testing was used to compare mean levels of the difference between DNAm age and chronologic age for pre- and post-menopausal groups. We examined the outcome “age acceleration”, calculated using the residuals of the regression of DNAm age versus chronologic age, because it is age-adjusted and independent of cell distribution. Multivariate linear regression models were used to examine for associations between age acceleration and each of our covariates.

Results: Our sample included women aged 19-90 years (mean age 50.7, SD 11.8), with 114 nulliparous women. We confirmed that DNAm age in breast tissue is strongly correlated with chronologic age (ρ=0.89, p<0.0001). The difference between DNAm age and chronologic age is greater at earlier ages, and is significantly greater in premenopausal women (mean 8.9 years, SE 0.04), compared with postmenopausal women (mean 2.7 years, SE 0.05) (p<0.0001). Age acceleration was significantly associated with earlier age at menarche (β=-0.395 for each year, p=0.036). For women with limited total years of exposure to estrogen (<19 years), there was a significant association between age acceleration and total estrogen exposure and β=0.673 for each year, p=0.028).

Conclusion: Acceleration of epigenetic age in breast tissues occurs in healthy women and is most pronounced in the pre-menopausal period. Earlier age at menarche and total years of estrogen exposure are associated with higher degree of acceleration, suggesting that cumulative estrogen exposure drives this process.

Citation Format: Sehl ME, Henry JE, Storniolo AM, Horvath S, Ganz PA. Hormonal factors associated with elevation of DNA methylation age in breast tissue of healthy women [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-08.
Abstract P1-16-06: Improved survival of patients with metastatic breast cancer in routine care is restricted to tumors with positive hormone receptor and/or Her2-expression. Survival analysis of 1,321 patients treated between 1995 and 2017 in oncology group practices
Authors: Weide R , Rendenbach B , Laubenstein H-P , Braun U , Hünermund K , Burkhard O , Ehscheidt P , Feiten S , Chakupurakal G , Friesenhahn V , Kleboth K , Köppler H , Lutschkin J , Thomalla J , van Roye C , Heymanns J
Published: May 2019

Introduction: 18,000 women die due to metastatic breast cancer in Germany per year. Median survival is 20–28 months after diagnosis. The question we wanted to answer was whether survival has improved in routine care?

Methods: Retrospective analysis of all patients with metastatic breast cancer who were treated between 06/1995-12/2017 in 5 community-based oncology group practices in Germany.

Results: 1,321 patients were analyzed with a median age of 62 (23–100). Localizations of metastases were distributed as follows: 49% visceral, 33% bone, 6% CNS, 12% others. 79% were hormone-receptor-positive, 20% Her2-positive, 9% triple-negative. Median overall survival was 37 months (95% Confidence Interval: 34–40), survival probability after 5 years 32.5%. Survival was significantly correlated with localizations of metastases, number of metastasized organs, disease free survival since initial diagnosis, hormone- and Her2-receptor status and age. Patients with hormone-receptor-positive tumors had a median overall survival of 39 months, Her2-positive patients of 45 months and triple-negative patients of 20 months. 86% of hormone-receptor-positive patients received antihormonal therapy. 81% of Her2-positive patients received anti-Her2 therapy. Overall survival according to treatment period 1995-2000, 2001-2005, 2006-2011, 2012-2017 was 34, 35, 37 and 38 months respectively. OS of patients with hormone-positive tumors according to treatment period was 35, 43, 38, and 42 months respectively. OS of patients with Her2-positive tumors according to treatment period was 39, 29, 51, and 54 months respectively. OS of patients with triple-negative tumors according to treatment period was 7, 11, 16, and 25 months respectively.

Conclusions: Improved survival of patients with metastatic breast cancer in routine care is strongly restricted to hormone receptor- and Her2-positive tumors most likely due to improved targeted therapies directed against the estrogen-receptor and Her2.

Citation Format: Weide R, Rendenbach B, Laubenstein H-P, Braun U, Hünermund K, Burkhard O, Ehscheidt P, Feiten S, Chakupurakal G, Friesenhahn V, Kleboth K, Köppler H, Lutschkin J, Thomalla J, van Roye C, Heymanns J. Improved survival of patients with metastatic breast cancer in routine care is restricted to tumors with positive hormone receptor and/or Her2-expression. Survival analysis of 1,321 patients treated between 1995 and 2017 in oncology group practices [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-16-06.
Abstract P1-17-08: High-dose chemotherapy and immunotherapy in premenopausal breast cancer patients with more than 10 axillary nodes (PBC+10N). Long-term follow-up of a phase II study
Authors: Recchia F , Candeloro G , Rea S
Published: May 2019

Background: PBC+10N have a high risk of relapse. Experimental studies suggest that high expression of vascular endothelial growth factor (VEGF) promotes tumor progression through neoangiogenesis and that natural killer (NK) cells mediate lytic activity against cancer cell lines. In a phase I-II study, we have shown that low-dose interleukin-2 (IL-2) and 13-cis retinoic acid (RA) increased NK cells and decreased VEGF, in patients with advanced cancer and a clinical benefit from chemotherapy (Clin Cancer Res 7: 1251, 2001). We assumed that IL-2 and RA, increasing NK and decreasing VEGF, could improve disease-free survival (DFS) and overall survival (OS) in PBC+10N. Primary endpoint was the evaluation of NK cells and VEGF; secondary endpoints were DFS, OS and toxicity. Methods: 34 patients with PBC+10N, after high-dose chemotherapy and peripheral blood progenitor cell transplantation were entered into the study. They were given hormonal therapy if needed and subcutaneous IL-2, 1.8 X 106 IU and oral RA, 0.5 mg/Kg for 5 days/week, 3 weeks/month, until progression. NK cells, VEGF, response and toxicity were assessed every 4 months. Results: After a median follow-up of 120 months (range 69-209), a total of 41 courses of high-dose chemotherapy and 60 courses of immunotherapy were delivered. A statistically significant improvement of NK cells [from a mean of 302 ± 75/mm3 to a mean of 582 ± 72/mm3 (p < 0.001)] and a decrease of VEGF [from a mean of 525 ± 68 pg/mm3 to a mean of 155 ± 13 pg/mm3, (p < 0.001)], were observed. 18-years DFS and OS were 29% and 32%, respectively. A significant improvement, with respect to NCI SEER data (*), was observed in the 5-year OS rate: 55% vs. 6% No WHO grade 3 or 4 toxicity was observed, while grade 2 cutaneous toxicity and fever occurred in 20% and 13% of patients, respectively. Conclusions: Our data show that immunotherapy with IL-2/RA, may determine, with an acceptable toxicity profile, a statistically significant improvement of NK cells, a decrease of VEGF, and better 5-year survival rates with respect to NCI SEER data.

Citation Format: Recchia F, Candeloro G, Rea S. High-dose chemotherapy and immunotherapy in premenopausal breast cancer patients with more than 10 axillary nodes (PBC+10N). Long-term follow-up of a phase II study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-17-08.