bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1-07-06: Immune signatures define and affect prognosis in triple-negative breast cancer subtypes
Authors: Bottai G , Balazs G , Nagy A , Pusztai L , Szallasi Z , Reis-Filho JS , Santarpia L
Published: May 2019

Background: The tumor immune microenvironment is formed by many distinct and interacting cell populations, and its composition may predict patient's prognosis and response to therapies. Triple negative breast cancer (TNBC) is a heterogeneous disease in which different genomic subgroups have been described (Lehmann, et al. J Clin Invest.2011). Our aim was to integrate the composition of the tumor immune microenvironment with the molecular TNBC subtypes.

Methods: We retrospectively analyzed the composition and the functional orientation of the immune microenvironment of 963 TNBC tumors clustered in 4 main TNBC subgroups (Basal-Like [BL1/2], Immunomodulatory [IM], Mesenchymal/Mesenchymal Stem-Like [MS], Androgen Receptor [AR]) from independent cohorts using transcriptomic profiling. TNBC were stratified based on 9 different immune signatures (Natural Killer [NK], Dendritic Cells [DC], T-Cells [TC], B-Cells [BC], T-Cytotoxic [TC], Interferon [IF], Nuclear Factor-kB [NF-kB], anti-tumor Macrophages [M1] and pro-tumor Macrophages [M2]. We validated our findings using immunohistochemistry.

Results: We report that TNBC molecular subgroups and specific microenvironmental immune signatures are highly correlated. The IM was enriched of almost all the immune modules. On overall TNBC population, the TC (P = 0.01), IF (P = 0.007) and M1 (P = 0.001) signatures were associated with good prognosis. The BL subgroup with a good prognosis was characterized by overexpression of genes specific to M1-macrophages (P = 0.004) and TC-lymphocytes (P = 0.01). In contrast, the poor-prognosis MS expresses markers of cells of monocytic origin and significantly associated with the M2 signature (P = 0.01). The MS subgroup also displays an inflammatory and immunosuppressive signature. Pathological examination revealed that the MS subtype is characterized by a high density of pro-tumor macrophages that likely produce chemokines and cytokines which favor tumor-associated inflammation, resulting in a poor prognosis. In contrast, the AR exhibits low immune and inflammatory signatures.

Conclusions: The distinct immune orientations of the TNBC molecular subtypes pave the way for tailored immunotherapies.

Citation Format: Bottai G, Balazs G, Nagy A, Pusztai L, Szallasi Z, Reis-Filho JS, Santarpia L. Immune signatures define and affect prognosis in triple-negative breast cancer subtypes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-07-06.
Abstract P2-01-27: Sentinel lymph node biopsy by contrast-enhanced ultrasonography with sonazoid in patients with breast cancer - Prospective multicenter study
Authors: Shimazu K , Ito T , Uji K , Miyake T , Motomura K , Noguchi S
Published: May 2019

Background: The aim of this prospective study is to evaluate feasibility of the periareolar injection of contrast agent (Sonazoid (SNZ)) followed by ultrasonography (US) for identification of sentinel lymph node (SLN) in breast cancer patients with clinically negative node.

Patients and Methods: Patients with T1-2N0M0 breast cancer were recruited in this study. They received the periareolar injection of SNZ followed by US to identify contrast-enhanced SLN. Fine needle aspiration biopsy (FNAB) was done for each CE-SLN. Then, they underwent SLN biopsy with the conventional method, blue dye and/or radiotracer (B/R).

Results: In almost all cases, contrast-enhanced lymphatic vessels were clearly visualized US soon after the periareolar injection of SNZ, and SLN, into which lymphatic flow was draining, was easily identified. The identification rate of SLN was 98% (98/100) by SNZ and 100% (100/100) by B/R. The number of SLNs identified by SNZ (mean per patient, 1.52) was significantly (P < 0.001) lower than that of those by B/R (2.22). Twenty-five patients had at least one metastasis in the SLNs identified by SNZ and/or B/R. In these patients, SLNs (n=39) identified by both SNZ and B/R showed a significantly (P < 0.0001) higher positivity (74.4%) for metastases than those (n=19) identified by B/R alone (21.1%).

Conclusion: Identification of SLN by periareolar injection of SNZ followed by US is a technically easy method and the identification rate of SLN was as high as 98%, being comparable to the conventional B/R. SLNs detected by SNZ seem to represent the true SLNs which first receive lymphatic flow from the tumor among the SLNs detected by B/R.

Citation Format: Shimazu K, Ito T, Uji K, Miyake T, Motomura K, Noguchi S. Sentinel lymph node biopsy by contrast-enhanced ultrasonography with sonazoid in patients with breast cancer - Prospective multicenter study [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 P2-01-27.
Abstract P2-04-15: Osteoclasts derived from dendritic cells by 4T1 T cells millieu maintain antigen presenting capability and osteolytic activity
Authors: Bonomo A , Monteiro AC
Published: May 2019

This abstract was withdrawn by the authors.
Abstract P2-05-26: uPA/PAI-1 and adjuvant chemotherapy decision-making in early breast cancer
Authors: Deluche E , Venat-Bouvet L , Leobon S , Fermeaux V , Aubard Y , Saïdi N , Jammet I , Tubiana-Mathieu N
Published: May 2019

Background: Adjuvant chemotherapy decisions are relatively simple using clinicopathological parameters (Goldhirsch et al. 2007), some cases require the addition of biomarkers as in patients with node negative or micrometastatic (N0), grade II (GII) breast cancer. The objective of this study was to evaluate the impact of uPA/PAI-1 compared to classical criteria +/- KI67 in adjuvant treatment decision-making in this population.

Methods: This retrospective study included patients, treated from March 2008 to May 2016 in the Department of Medical Oncology at Limoges University Hospital (France). Ki67 and uPA/PAI-1 were analyzed on the initial specimen tumor. Optimal cut-off of Ki67 was defined at 20% (Coates et al. 2015). The positivity thresholds of uPA and PAI-1 were 3 ng/mg and 14 ng/mg respectively (Look et al. 2002). A positive uPA/PAI-1 level was defined as the elevation of at least one of these markers above the positivity threshold. All clinicopathological parameters were recorded prospectively.

Results: 2364 patients with breast cancer were screened. Among these patients, 256 N0, GII breast cancer patients were included with a median age of 62 years (32-87). Discordance between the two markers uPA/PAI-1 and KI67 was observed in 58% of tumors. Adding KI67 to the other classical clinicopathological parameters, 143 cases were defined as high risk versus 111 cases without KI67; low risk were defined in 113 cases versus 145 cases without KI67. Considering Ki67 status, the indication to perform adjuvant chemotherapy was increased by 29% compared to clinicopathological parameters. uPA/PAI-1 level was positive in these 143 high risk tumors in 93 cases and negative in 50 cases; in the 113 low risk tumors uPA/PAI-1 was positive in 72 cases and negative in 41 cases. uPA/PAI-1 increased indication to perform adjuvant chemotherapy by 15% compared to St Gallen criteria (including KI67) and by 49% compared to St Gallen criteria (excluding KI67). Using these two markers the final decision of chemotherapy by the multidisciplinary board was increased by 3% compared to St Gallen criteria (including KI67).

Conclusions: This study highlighted that uPA/PAI-1 and Ki67 assessment provides additional information for adjuvant chemotherapy decision-making. This study confirms the difficulty to assess the level of importance (weighting) of these biomarkers in adjuvant chemotherapy decision-making. The use of uPA/PAI-1 was feasible, cost-effective in N0, GII breast cancer's patients.

Citation Format: Deluche E, Venat-Bouvet L, Leobon S, Fermeaux V, Aubard Y, Saïdi N, Jammet I, Tubiana-Mathieu N. uPA/PAI-1 and adjuvant chemotherapy decision-making in 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 P2-05-26.
Abstract P3-04-12: Both spliced and unspliced XBP1 regulates breast cancer cell fate response to antiestrogen via NFkappaB signaling
Authors: Clarke R , Hu R , Warri A , Jin L , Zwart A , Riggins R , Fang H-b
Published: May 2019

Unfolded protein response (UPR), a stress-induced survival mechanism, may be used by cancer cells to avoid cell death. Antiestrogen therapy, widely applied in the treatment of estrogen receptor-positive (ER+) breast cancer, induces endoplasmic reticulum stress (EnR stress) that leads to activation of each of the three arms of the UPR. One critical prosurvival activator that is regulated by two arms of the UPR is the transcription factor X-box binding protein 1 (XBP1). XBP1 exists in two isoforms, the transcriptionally inactive unspliced XBP1(U) and the spliced, active XBP1(S). Overexpression of XBP1(S) confers estrogen independence and antiestrogen resistance in ER+ breast cancer cells and XBP1(S) expression correlates with poor clinical responsiveness to Tamoxifen in ER+ breast tumors. However, the underlying signaling mechanisms regulated by XBP1, which may mediate its effects on antiestrogen resistance, are unknown. We show that depletion of endogenous XBP-1 by siRNA increases apoptosis, decreases autophagy, requires down-regulation of p65/RelA, a component of the pro-survival NFκB complex. Using novel spliced and non-spliceable forms of XBP1, we show that XBP1(U) and XBP1(S) both regulate NFκB activity via ERα signaling in breast cancer cells. XBP1(S), but not XBP1(U), also can regulate p65/RelA expression independent of ERα. Antiestrogen resistance as conferred by XBP1 overexpression in MCF-7 cells requires the activation of NFκB signaling; inhibition of NFκB signaling by either the small molecule NFκB inhibitor Parthenolide or p65/RelA siRNA sensitizes XBP1 overexpressing cells to Tamoxifen. The activation of XBP1 and the downstream NFκB signaling is likely to contribute to the TMEM33 overepxression induced apoptosis, as both NFκB signaling and XBP1(S) are elevated in TMEM33 overexpressed MCF7 cells. Thus, we have identified a critical regulatory link between the UPR/XBP1 pathway and pro-survival NFκB signaling that is a major contributor to endocrine responsiveness in ER positive breast cancer.

Citation Format: Clarke R, Hu R, Warri A, Jin L, Zwart A, Riggins R, Fang H-b. Both spliced and unspliced XBP1 regulates breast cancer cell fate response to antiestrogen via NFkappaB signaling [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 P3-04-12.
Abstract P3-04-13: Protein tyrosine kinase 6 (PTK6) promotes survival of endocrine therapy-resistant ER+ breast cancer cells
Authors: Irie HY , Park SH , Katsyv I , Zhang W , Nayak A
Published: May 2019

Background/Rationale: The non-receptor tyrosine kinase PTK6/Brk is highly expressed in the ER+/Luminal breast cancer subtypes. PTK6 expression has prognostic significance for patients with ER+ disease; higher transcript levels are associated with poorer survival. The functions of PTK6 in the context of ER+ breast cancer and sensitivity to endocrine therapy have not been explored. We sought to determine the functional roles of PTK6 in ER+ breast cancer cells, including those that are relatively resistant to current endocrine therapies. Methods/Results. We modulated the expression of PTK6 using both gain- and loss-of-function approaches. Enhanced expression of PTK6 in Tamoxifen-sensitive ER+ breast cancer cells was sufficient to confer relative Tamoxifen resistance. Furthermore, downregulation of PTK6 in ER+ breast cancer cells, including those that have acquired resistance to Tamoxifen, induced apoptosis, as evidenced by an increase in AnnexinV+ cells and increased levels of cleaved PARP. PTK6 downregulation impaired growth of Tamoxifen-resistant variants of ER+ MCF7 and T47D cells (MCF7TamR and T47DTamR) in 3D Matrigel culture, and virtually abrogated primary tumor growth of MCF7TamR xenografts. Mechanistically, p38MAPK activation is critical for PTK6 downregulation-induced apoptosis of ER+ breast cancer cells, as p38 inhibition partially rescues cells from PTK6 shRNA-associated apoptosis. Conclusions: Our studies highlight the critical role that PTK6 plays in the survival of ER+ breast cancer cells, including those that are resistant to endocrine therapy. Enhanced PTK6 expression in ER+ breast cancer cells is sufficient to promote endocrine therapy resistance, which could contribute to the poorer prognosis associated with higher PTK6 expression in ER+ patient tumors. As small molecule PTK6 inhibitors are becoming available, our studies support further evaluation of PTK6 as a candidate therapeutic target for endocrine therapy resistant ER+ breast cancers.

Citation Format: Irie HY, Park SH, Katsyv I, Zhang W, Nayak A. Protein tyrosine kinase 6 (PTK6) promotes survival of endocrine therapy-resistant ER+ breast cancer cells [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 P3-04-13.
Abstract P4-03-11: Fibroblasts isolated from the “normal-like” tissue adjacent to breast tumours suppress healthy epithelial progenitor cell proliferation while supporting tumour cell growth
Authors: Chatterjee S , Berdnikov A , Lee-Wing V , Safneck J , Buchel E , Raouf A
Published: May 2019

The tissue adjacent to breast tumors has been referred to as “normal-like” tissue despite exhibiting many alterations at epigenetic and gene expression levels consistent with enhanced proliferation and wound healing signatures. However, the influence of such alterations on the proliferation and differentiation of healthy breast progenitors is currently unknown. Fibroblasts are a major component of microenvironment for the healthy and malignant breast cells. We therefore, isolate fibroblast from primary breast tumors, tissue adjacent to tumors (TAT) and the healthy breast tissue and examine their ability to support proliferation of healthy and malignant breast cells. To characterize the TAT samples we first utilized clonal co-culture assays using breast cells obtained from the healthy breast tissue (reduction mammoplasty sample, RM) and the healthy fibroblasts. Our results suggested that the TAT samples surprisingly contained significantly decreased pool of progenitors compared to the RM samples. In order to study the underlying mechanism, we characterized fibroblasts derived from either the breast tumours (TAFs) or the TAT samples (TATF) or the RM normal samples (NAFs) and assessed their role on breast progenitor cell functions. Fibroblasts were isolated from the ER+ and ER- breast tumours and their adjacent breast tissue. We observed that matrigel co-cultures consisting of RM samples and NAFs led to a 5.5-fold expansion of the progenitors, whereas the co-cultures of TAT or the RM samples with either TAFs or TATFs failed to show expansion of epithelial progenitors. The comparative secretome analysis of the NAFs and the TATFs identified TGFβ as a candidate molecule primarily secreted only by the TATFs and not by NAFs. Interestingly, blocking TGFβ signaling restored both TAFs' and TATFs' ability to support the expansion of healthy progenitors in matrigel cultures. Lastly, we found that TAFs were able to enhanced breast cancer cell proliferation in vivo and in vitro but to a lesser extent than the TAFs. Our observations suggest that the tissues adjacent to breast tumours are transformed into a TGFβ-enriched environment that is supportive of breast tumour growth while suppressing the proliferation and differentiation potentials of the healthy breast progenitors. Our data also suggest that the use of TGFβ blockers may be important in reducing risk of local breast tumour recurrence.

Citation Format: Chatterjee S, Berdnikov A, Lee-Wing V, Safneck J, Buchel E, Raouf A. Fibroblasts isolated from the “normal-like” tissue adjacent to breast tumours suppress healthy epithelial progenitor cell proliferation while supporting tumour cell growth [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 P4-03-11.
Abstract P4-19-01: Non-metastatic and metastatic breast cancer patients' priorities when considering a treatment decision
Authors: Buzaglo JS , Miller MF , Longacre M , Kamal AH
Published: May 2019

This abstract was not presented at the symposium.
Abstract P4-19-07: Fertility concerns in young women after diagnosis of breast cancer: Experience of a breast cancer unit in México
Authors: Campos-Gomez S , Campos-Gomez KA , Ovando-Trujillo A , Palacios-Gutierrez F
Published: May 2019

Background

Nearly 30% of all new breast cancer diagnoses occur in pre-menopausal women and about 7% of diagnoses occurring in women aged 40 years or less. Breast cancer treatment can increase the risk of early menopause and infertility. It is the major source of distress and concern form many young breast cancer patients who have no finished their families and have plans for childbearing.

Methods

As part of multidisciplinary approach in the Breast Cancer Unit at Centro Oncologico Estatal ISSEMYM an evaluation psychosocial aspects of sexuality, fertility and menopause after diagnosis of breast cancer has been implemented.

We conducted an exploratory study to better understand fertility concerns, the role of fertility in the treatment decisions and chemotherapy acceptance in a cohort of young women newly diagnose breast cancer evaluated in a Breast Cancer Unit. We invited eligible women to participate, fertility concerns was the primary end point

Results

A total of 52 women were evaluated. Of these, we exclude 2 patients they have stage IV disease at re staging. Thus 50 women were included in the analyses. Median age at diagnosis was 36 years (range 23 to 40 years). 86% had children already at the time of breast cancer diagnosis. Only 4 participants (8%) reported that before their breast cancer diagnosis, they wanted to have future or additional children. Whereas forty six (92 %) did not. Of these patients 85% don't want to have children because of prior decision and 20% because fear of cancer recurrence. Forty nine patients would agree to receive chemotherapy (98%) and 51% would accept a risk of infertility of 76-100%. This acceptance was dependent on already having children. 68% would accept it only for ≥20% gain in cure.

Conclusion

Our study represents one of the first prospective evaluations of fertility concern in young women with recently diagnosed breast cancer in a Public Hospital in México. For the majority of young patients with breast cancer, cure remains their first priority. Most of the women have child before diagnosis and only 8% want to have additional children.

Citation Format: Campos-Gomez S, Campos-Gomez KA, Ovando-Trujillo A, Palacios-Gutierrez F. Fertility concerns in young women after diagnosis of breast cancer: Experience of a breast cancer unit in México [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 P4-19-07.
Abstract P4-21-40: In vitro and in vivo activity of HER2-targeted antibody-liposomal doxorubicin conjugate MM-302 in HER2-intermediate tumors
Authors: Geretti E , Espelin C , Adiwijaya B , Coma S , Koncki Z , Sumner P , Dumont N , Garcia G , Bloom T , Janovsky J , Reynolds J , Campbell K , Moyo V , Molnar I , LoRusso P , Krop I , Miller K , Ma C , Munster P , Wickham T
Published: May 2019

This abstract was withdrawn by the authors.
Abstract P5-02-04: Study on over-diagnosis of high-precision breast cancer screening ∼ Consideration from epidemiological point of view
Authors: Takebe K , Arai T
Published: May 2019

In breast cancer screening, it has been attempted to combine US with MMG. For relatively small breasts and dense breasts, there is the opinion that this combination is useful. On the other hand, the problem of over-diagnosis of breast cancer screening has been raised. We've been breast cancer screening with US/MMG combination method since 2005. The results were examined from the epidemiological point of view.

Breast cancer discovery rate through US/MMG screening at our facility from 2005 to 2014 was considered. The medical examination was performed on 35,353 women.

Kagawa Prefecture, in which our facility is located has had 100 percent breast cancer registration for more than 10 years. We have compared the breast cancer registration of 2013 with our examination results.

Asymptomatic breast cancer detection rate in our breast cancer screening was 0.6%. ４６% of the detected cancer was DCIS. Low-grade DCIS (Van Nuys 1 and 2) accounted for three-quarters of DCIS. In invasive carcinoma, 10 mm or less of luminal A type was 17%, other luminal types 19%, non-luminal types 5% and unclassified 6%. If our facility's highly precise breast cancer medical examination were performed throughout Kagawa Prefecture, DCIS would be found in 860 cases, 10 mm or less of luminal A type found in 276, other luminal type found in 320 and non-luminal type found in 70 cases per year.Compared to the Kagawa Prefecture breast cancer registered in 2013, DCIS was 6.6 times larger than the registered data, 10 mm or less of luminal A 2.9 times larger, other luminal types 1.1 times larger, and non-luminal types 1.2 times larger. The differences between the registered data and our findings for DCIS and 10mm or less of luminal A type are remarkable.

With the US/MMG combination method, the detection rate of DCIS and 10 mm or less of luminal A type have been excessive. Many type of DCIS and tiny luminal A type must exist latently. When performing a high-precision breast cancer screening, it is necessary to note such over-diagnosis. Furthermore, it is also necessary to re-examine the pathology diagnostic criteria of DCIS.

Citation Format: Takebe K, Arai T. Study on over-diagnosis of high-precision breast cancer screening ∼ Consideration from epidemiological point of view [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 P5-02-04.
Abstract P5-14-09: Luminal A breast cancer: Is it really a “good prognosis” disease? Prelimary results of the GIM-13 - AMBRA study
Authors: Cazzaniga ME , Mustacchi G , De Laurentiis M , Garrone O , Donadio M , Del Mastro L , Latini L , Livi L , Michelotti A , Montemurro F , Natoli C , Riccardi N , Turletti A , Giordano M , De Placido S , Biganzoli L , Pronzato P , Marchetti P
Published: May 2019

This abstract was not presented at the symposium.
Abstract P6-01-13: BCAP31 promotes EMT and metastasis upon nutrient deprivation through autophagy in breast cancer
Authors: Fu W , Sun H , Gao S , Li L , Jin W
Published: May 2019

This abstract was not presented at the symposium.
Abstract P6-07-19: An alteration of hormonal receptor status throughout tumor progression related to prognosis in breast cancer patients
Authors: Lee E-S , Kim J , Yoo T-K , Kim Y , Han J , Kang YJ , Choi J , Rhu J , Lee H-B , Han W , Noh D-Y , Moon H-G
Published: May 2019

Purpose

We aimed to identify whether hormonal receptors change throughout tumor progression, because this may influence management and influence prognosis in breast cancer patients.

Patients and Methods

From the institution's database, we collected data of 963 patients who developed relapse during their follow-ups. To determine estrogen receptor(ER) and progesterone receptor (PR), we retrospectively reviewed immunohistochemical(IHC) results in both primary and relapsed tumors.

Results

Among a total of 963 patients, 280 and 683 patients experienced locoregional relapse only and distant metastasis irrespective of locoreginal relapse, respectively. ER in 650 patients and PR in 590 patients from both primary tumor and relapse were identified, revealing a change in 157 (24.2%) and 154 (26.1%) patients, respectively. In patients with distant metastasis, assessment of ER and PR showed an alteration in 86 and 56 patients, respectively. The overall survival related to the change of ER and PR status in primary tumor and relapse was significantly different (log rank, P<0.001 in both ER and PR status). In addition, women with hormone receptors negative primary tumors that changed to hormone receptors positive tumors who received anti-hormonal therapy after relapse showed a statistically significant good overall survival (p<0.001) compared with women who had constant ER-negative tumors.(cox regression, hazard ratio 2.32 ; 95% CI, 1.91 to 3.01)

Conclusion

The breast cancer showed alterations of hormone receptor status throughout tumor progression, hat were related to the strategy of treatment and significantly influences survival. Therefore, investigations of hormone receptor at relapse are essential and helpful in breast cancer patient management.

Citation Format: Lee E-S, Kim J, Yoo T-K, Kim Y, Han J, Kang YJ, Choi J, Rhu J, Lee H-B, Han W, Noh D-Y, Moon H-G. An alteration of hormonal receptor status throughout tumor progression related to prognosis in breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-19.
Abstract P6-07-23: The ELK3 expression is positively associated with interferon signaling molecules in triple-negative breast cancer
Authors: Song IH , Heo S-H , Kim Y-A , Park IA , Park HS , Choi SK , Park SY , Bang WS , Gong G , Lee HJ
Published: May 2019

This abstract was withdrawn by the authors.
Abstract P6-10-07: Long survival of patients with locally advanced breast cancer on combined neoadjuvant chemotherapy and immune potentiation: Modern lessons from an old study
Authors: Pohlmann PR , van Cruijsen H , Stam AGM , Lougheed SM , van den Eertwegh AJM , Hoekman K , Scheper R , Buter J , van der Hoeven JJM , van der Wall E , Pinedo HM , de Gruijl TD
Published: May 2019

This abstract was not presented at the symposium.
Abstract P6-17-04: Mechanisms of drug sensitization by DHA on doxorubicin-resistant human breast adenocarcinoma
Authors: Rahman MM , Veigas JM , Auhtit A , Chowdhury W
Published: May 2019

This abstract was not presented at the symposium.
Abstract BS1-1: High resolution intravital imaging of the mechanism of how breast cancer initiates and sustains systemic dissemination
Authors: Condeelis J
Published: May 2019

Multiphoton microscopy of live animals (IVI) has revolutionized our understanding of cancer metastasis. IVI demonstrates that TMEM, the intravasation doorway, composed of a three cell complex: Mena-Hi tumor cell, endothelial cell and Tie2-Hi/VEGF-Hi macrophage, is the only site in breast tumors where tumor cell intravasation occurs1. During tumor progression, macrophage progenitor cells undergo unidirectional transition from migratory to TMEM-associated macrophages2. During and after this macrophage programming, tumor cells migrate with macrophages and chemotax with high persistence to blood vessels under the control of HGF gradients3 arriving at TMEM1. The TMEM structure itself, as well as the signaling pathways unique to tumor cells interacting with TMEM, have been validated as prognostic markers for predicting metastasis in breast cancer patients4-6. These were the first markers of metastasis in clinical use derived from multiphoton intravital imaging.

TMEM are found in both primary and metastatic tumor sites of breast cancer7 and in primary and metastatic sites of pancreatic ductal and neuro-endocrine tumors. Clinical trials of TMEM inhibitors, targeting TMEM in both primary and secondary sites8,9, are now underway in breast cancer patients (clinical trials study number NCT02824575). As tumor cells interact with TMEM, MenaINV. expression in the tumor cells occurs in response to macrophage-induced NOTCH signaling10, which drives invadopod assembly/ function, and metastatic seeding11,12. MenaINV expression is necessary for invadopod-mediated transendothelial migration during intravasation at TMEM13 and assures the efficient dissemination of seeding competent and non-dividing tumor cells which, after a delay, contribute to metastatic recurrence at multiple systemic sites. These findings support TMEM as a critical therapeutic target for inhibiting breast cancer metastasis.

1.Harney, A.S. et al. (2015) PMC4560669

2.Arwert, E.N. et al. (2018) PMC5946803

3.Leung, E. et al. (2017) PMC5426963

4.Karagiannis, G.S. et al (2016) PMC4893654

5.Rohan, T.E. et al. (2014) PMC4133559

6.Sparano, J.A. et al. (2017)PMC5678158

7.Entenberg, D. et al. (2018)PMC5755704

8.Harney, A.S. et al. (2017)PMC5669998

9.Karagiannis, G.S. et al. (2017) PMC5592784

10.Pignatelli, J. et al. (2016) PMC5129016

11.Eddy, R.J. et al (2017) PMC5524604

12.Linde, N. et al. (2018) PMC5750231

13.Pignatelli, J. et al.(2014) PMC4266931

Citation Format: Condeelis J. High resolution intravital imaging of the mechanism of how breast cancer initiates and sustains systemic dissemination [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 BS1-1.
Abstract BS1-2: Neutrophil extracellular traps promote breast cancer metastasis
Authors: Egeblad M
Published: May 2019

Cancer cells from a primary tumor can disseminate to other tissues, but remain dormant and clinically undetectable for many years. Little is known about the cues that cause these dormant cells to “awaken”, resume proliferation, and develop into metastases. Using mouse models, we have found that sustained lung inflammation caused by tobacco smoke exposure or nasal instillation of lipopolysaccharide converted disseminated, dormant cancer cells to aggressively growing metastases. Using intravital imaging techniques, which allow for long-term time-lapse imaging of cancer cells and surrounding host cells in living mice, we observed that sustained inflammation induced the formation of neutrophil extracellular traps (NETs). NETs are pathogen-trapping structures generated by expulsion of the neutrophil's DNA with associated proteolytic enzymes in response to e.g., infections. We confirmed that NETs were present in clinical samples of breast cancer lung metastases. Mechanistic analysis revealed that NETs were required for awakening dormant cancer and specifically that two NET-associated proteases, neutrophil elastase and matrix metalloproteinase 9, sequentially cleaved laminin. The proteolytically remodeled laminin induced proliferation of dormant cancer cells by activating integrin alpha-3 beta-1 signaling. We generated antibodies against NET-remodeled laminin and these prevented awakening of dormant cells in mice. In addition, pharmacological inhibition of NET formation or digestion of NETs with DNase I-coated nanoparticles also markedly reduced awakening and lung metastases in mice. Our data suggest that induction of NETs is an important host-mediated mechanism of promoting metastasis and a potential therapeutic target to prevent preventing dormant cell awakening and prolong the survival of cancer patients.

Citation Format: Egeblad M. Neutrophil extracellular traps promote breast cancer metastasis [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 BS1-2.
Abstract ES10-1: Recurrent ESR1 mutations activating mutations in breast cancer
Authors: Jeselsohn R
Published: May 2019

Endocrine treatments are the cornerstone treatments in estrogen receptor positive (ER+) breast cancer. Despite their efficacy, resistance to endocrine treatments remains an important clinical challenge. A number of years ago, recurrent estrogen receptor ligand binding domain (LBD) mutations were identified as the most common genomic mechanism of acquired resistance to endocrine treatment in metastatic breast cancer. These mutations were found in about 20% of ER+ metastatic tissue specimens and in more than 30% of patients with metastatic ER+ breast cancer when testing circulating tumor DNA. Pre-clinical studies showed that these mutations lead to constitutional ligand independent transcriptional activity and tumor growth. Recently, we showed that the ER mutations have neomorphic properties that promote metastases. Clinical data, derived mainly from retrospective analyses of clinical trials, indicate that the ER mutations confer resistance to aromatase inhibitors and fulvestrant, and decreased overall survival. A recent study also showed that the Y537S LBD ER mutation is acquired during fulvestrant and palbociclib treatment. Collectively, the ER mutations are important drivers of resistance standard endocrine treatments and confer worse outcomes in ER+ metastatic breast cancer. Clinical trials stratifying patients by ER mutant status or dedicated to patients with the ER mutations are needed to identify therapeutic strategies to target these mutations.

Citation Format: Jeselsohn R. Recurrent ESR1 mutations activating mutations in 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 ES10-1.
Abstract ES12-1: BRCA2 and control of transcription: R-loop dynamics
Authors: Venkitaraman A
Published: May 2019

Pathogenic germline mutations affecting the breast cancer genes, BRCA1 and BRCA2, predispose to cancers of the breast, ovary, and other tissues with a high penetrance. Cancer pathogenesis in mutation carriers has been linked to genomic instability following inactivation of the essential cellular functions of the encoded BRCA1 and BRCA2 proteins in DNA repair and the restoration of stalled DNA replication (reviewed in Venkitaraman, Science 343, 1470-5 (2014)). Here, I will discuss emerging evidence that links previously unrecognized functions of the BRCA proteins to carcinogenesis, focusing on BRCA2.

Increasing evidence indicates that heterozygosity for pathogenic BRCA2 mutations suffices for carcinogenesis in experimental models and in human mutation carriers (eg., Skoulidis et al., Cancer Cell 18, 499-509 (2010); Maxwell et al., Nature Commun 8, 319 (2017); Huang et al., Cell 173, 355-370 (2018)). Heterozygous mis-sense mutations in BRCA2 may act trans-dominantly to interfere with the nuclear transport of BRCA2/RAD51 complexes (Jeyasekharan et al., Nature Str Mol Biol 20, 1191-8 (2013)). We have reported recently a gene-environment interaction that may modify carcinogenesis in BRCA2 mutation carriers, wherein exposure to aldehydes, a pervasive class of endogenous and environmental toxins, selectively proteolyzes BRCA2, inducing haploinsufficiency for DNA repair and replication fork stability in cells bearing heterozygous truncating BRCA2 mutations (Tan et al., Cell 169, 1105-18 (2017)). BRCA2-deficient cells accumulate unscheduled RNA-DNA hybrids (R-loops) and genomic damage through an unexpected role of BRCA2 in promoting the switch from promoter-proximal pausing to transcription elongation by RNA polymerase II (Shivji et al., Cell Rep 22, 1031-1039 (2018)). These emerging functions have implications for the pathogenesis and therapy of cancers arising in patients who carry BRCA2 mutations.

Citation Format: Venkitaraman A. BRCA2 and control of transcription: R-loop dynamics [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 ES12-1.
Abstract ES4-2: Treatment morbidity and quality of life considerations
Authors: Whelan T
Published: May 2019

Partial breast irradiation was introduced to reduce treatment times, improve convenience of radiotherapy and reduce radiation exposure to the breast and surrounding normal tissues. A number of techniques have been developed including interstitial brachytherapy, single catheter-based brachytherapy, intraoperative therapy, and 3 dimensional conformal or intensity modulated radiotherapy. The toxicity profile of partial breast irradiation has been dependent on the different techniques used. In general acute toxicity has been less than that observed with whole breast irradiation, particularly for intraoperative approaches where radiotherapy is delivered at the time of breast conserving surgery. Reports of late toxicity have varied. The majority of trials have observed no increase in late toxicity with interstitial brachytherapy and intraoperative treatment when compared to whole breast irradiation. Some studies of 3D conformal radiotherapy have reported an increase in late radiation toxicity such as telangiectasia of the skin and subcutaneous fibrosis of the breast. Limited data are available on cosmetic outcome and quality of life. Again, results to date have varied with some studies reporting similar cosmetic results and others indicating an increase in adverse cosmesis with partial breast irradiation when compared to whole breast irradiation. This presentation will review mature results from completed trials and discuss radiobiological inferences and implications for clinical decision making.

Citation Format: Whelan T. Treatment morbidity and quality of life considerations [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 ES4-2.
Abstract ES5-2: Clinical and molecular profiles to identify who is at risk?
Authors: Dowsett M
Published: May 2019

The persistent risk of recurrence from ER-positive primary breast cancer has been known for many years. It was recently described in detail and in relation to baseline clinicopathologic factors in a meta-analysis by the EBCTCG. This involved nearly 63,000 patients that had been prescribed 5 years of endocrine therapy and had reached the end of that time recurrence-free (Pan et al, NEJM, 2017, 377, 1836). Among other things this revealed that even among patients with T1N0 disease 13% had a distant recurrence between years 5 and 20. Our group have previously created a Clinical Treatment Score (CTS) from nodal status, tumor size, grade, age and type of adjuvant endocrine treatment and validated this for estimating risk of distant recurrence from the time of diagnosis. Drawing on a training dataset of 4,735 patients from the ATAC trial and a validation set of 6,711 patients from the BIG1-98 trial we created the CTS5, a prognostic score of risk from year 5, that features the same factors as CTS other than type of endocrine treatment (Dowsett et al, JCO, 2018, 36, 1941). Of note, only 4/304 patients with one to three positive nodes that were categorized as low risk in the validation set had a distant recurrence between years 5 and 10. The CTS5 calculator can be accessed online at www.cts5-calculator.com.

There are several commercially available molecular profiles that estimate the risk of recurrence over years 0-10 after diagnosis in endocrine-treated primary breast cancer. In the TransATAC study some of these, including the EPClin and PAM50-ROR, show similar prognostic information over years 5-10 (after 5 years of endocrine therapy) as they do over years 0-5 (during endocrine therapy). In contrast, while the Oncotype Recurrence Score (RS) showed similar prognostic information to EPClin and PAM50-ROR in years 0-5 its performance in years 5-10 was substantially worse. Examination of the time-dependent prognostic relationship of each of the individual genes and modules in the RS showed that those patients with higher ER signaling had good prognosis before year 5 but poorer after year 5, suggesting that the cessation of endocrine therapy may lead to this poorer post-5 year outcome (Dowsett et al Clin Cancer Res, 2015, 21, 2763). A broad-based assessment of gene expression in the TransATAC sample set found that there was limited potential to identify a prognostic profile that performed substantially better after 5 years (Buus et al, Breast Cancer Res, 2018, 20, 103). One test, the 7-gene Breast Cancer Index, has reported on a relatively small sample set that it can predict the benefit or not from extended adjuvant endocrine therapy. Further validation studies of this are warranted as well as other tests that provide the same predictive information.

Citation Format: Dowsett M. Clinical and molecular profiles to identify who is at risk? [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 ES5-2.
Abstract ES8-3: Does breast cancer prevention need an 18th amendment? New evidence on alcohol and breast cancer
Authors: Terry M
Published: May 2019

Epidemiological studies have consistently supported an association between alcohol consumption and breast cancer risk for many years. Breast cancer guidelines from many societies, including the American Cancer Society, have also discussed reducing alcohol consumption to help prevent breast cancer. So why aren't more women aware of this association? This talk will review the latest evidence, including more recent mechanistic studies, about the association between alcohol intake and breast cancer as well as newer data about the lack of cardio protective benefit of modest alcohol intake. What evidence do we now have about whether the association with breast cancer risk and outcomes after diagnosis varies by time in life and intensity of drinking patterns?

Citation Format: Terry M. Does breast cancer prevention need an 18th amendment? New evidence on alcohol and 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 ES8-3.
Abstract ES9-1: Optimizing treatment of early stage triple negative breast cancer: Clinical challenges and new scientific horizons
Authors: DeMichele A
Published: May 2019

“Triple negative” breast cancer (TNBC) as defined by the lack of estrogen and progesterone receptors and absence of Her2-overexpression, is challenging due to its aggressive natural history and limited treatment options. However, significant progress has been made in the last decade in understanding the biological diversity of TNBC, its prognosis and approaches to successful treatment. For example, molecular classification by gene expression studies initially identified a basal molecular subtype enriched for TNBC, which was further refined to additional include 4 major subtypes: basal-like, mesenchymal, luminal androgen receptor and immune-enriched. In addition, clear associations between TNBC and mutations in DNA-repair-related genes, especially BRCA-1 and BRCA-2 have been elucidated. These findings have subsequently guided therapeutic development.

The early-stage setting has been the focus of much of this work, as it is clear that patients who have tumors that respond vigorously to chemotherapy preoperatively have a reduced likelihood of later metastatic recurrence compared to those who have poorly-responsive disease. Capitalizing on this knowledge, trials in the neoadjuvant setting have defined the importance of pathologic complete response (pCR) as a surrogate endpoint, and have shed light on differential effects of standard therapy (such as platinums), development of new targeted therapies (such as PARP inhibitors) and the role of immunotherapy.

The high rate of observed recurrence in patients who have high stage disease at diagnosis, or, in particular, residual disease after neoadjuvant therapy, has also led to the launch of clinical trials in the adjuvant and post-neoadjvuant setting designed to specifically address micrometastatic minimal residual disease and therapy resistance. The advantage of the post-neoadjvuant approach to trials amongst patients with residual disease is to decrease the size of adjuvant trials, and allow them to be focused within populations most at risk of recurrence, sparing those with good prognosis the need for additional, potentially toxic treatment.

Despite this progress, there are still many unanswered questions regarding optimal therapy and potential to improve outcomes in TNBC. This session will review the state of the science with regard to biology, new treatment approaches, and the value of both the neoadjuvant and post-neoadjvuant settings in developing optimal approaches to tailor therapy on the basis of risk stratification, reduce recurrence, and improve outcomes for women presenting with triple negative breast cancer.

Citation Format: DeMichele A. Optimizing treatment of early stage triple negative breast cancer: Clinical challenges and new scientific horizons [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 ES9-1.
Abstract ES9-3: Triple negative breast cancer: Current and future directions in metastatic patients
Authors: Chang J
Published: May 2019

Chemotherapy is the primary established systemic treatment for patients with triple-negative breast cancer (TNBC) with both early and metastatic disease. The poor prognosis of patients with TNBC have fostered a major effort to discover actionable molecular targets and other approaches to treat these patients. Massively parallel sequencing and other 'omics' technologies have revealed an unexpected level of heterogeneity of TNBCs and have led to the identification of potentially actionable molecular features in some TNBCs, such as germline BRCA1/2 mutations or 'BRCAness', as well as a subgroup with a high degree of tumor-infiltrating lymphocytes that also correlates with a lower risk of disease relapse and a higher likelihood of benefit from chemotherapy. Proof-of-principle studies with immune-checkpoint inhibitors in advanced-stage TNBC have yielded promising results, indicating the potential benefit of immunotherapy for patients with TNBC. Additional data from trials with antibody drug conjugates have yielded promising results. We discuss the most relevant molecular findings in TNBC from the past decade and the most promising therapeutic opportunities.

Citation Format: Chang J. Triple negative breast cancer: Current and future directions in metastatic patients [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 ES9-3.