bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-09-01: MYC dysregulates mitotic spindle function in triple-negative breast cancer creating a dependency on TPX2
Authors: Goga A , Rohrberg J , Corella A , Taileb M , Kilinc S , Jokisch M-L , Camarda R , Zhou A , Balakrishnan S , Chang AN , Klein-Connolly H
Published: May 2019

Tumors that overexpress the MYC oncogene, including most receptor triple-negative breast cancers, frequently demonstrate aneuploidy, numerical chromosome alterations associated with highly aggressive cancers. Aneuploidy is also associated with rapid tumor evolution and poor patient outcome. We identify that MYC overexpression induces reversible defects in microtubule nucleation and mitotic spindle assembly, in TNBCs and other epithelial cells, promoting chromosome segregation defects, micronuclei and chromosomal instability (CIN). High TPX2 expression is permissive for mitotic spindle assembly and chromosome segregation in cells with MYC overexpression; whereas TPX2 depletion blocks mitotic progression, induces cell death and prevents tumor growth. Attenuating MYC expression reverses mitotic defects, even in established breast tumor cell lines, implicating an ongoing role for high MYC in the persistence of CIN in cancers. Our studies implicate the MYC oncogene as a regulator of spindle assembly and identify a new MYC-TPX2 synthetic-lethal interaction in TNBC that could represent a future therapeutic strategy in MYC-overexpressing cancers. Moreover, our studies suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution.

Citation Format: Goga A, Rohrberg J, Corella A, Taileb M, Kilinc S, Jokisch M-L, Camarda R, Zhou A, Balakrishnan S, Chang AN, Klein-Connolly H. MYC dysregulates mitotic spindle function in triple-negative breast cancer creating a dependency on TPX2 [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 P3-09-01.
Abstract P3-09-05: Withdrawn
Authors: Chakladar M , Nair MG , Prabhu JS , Cohen S , Srinivas ST , Lingadahalli SS
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Chakladar M, Nair MG, Prabhu JS, Cohen S, Srinivas ST, Lingadahalli SS. Withdrawn [abstract].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 P3-09-05.
Abstract P3-10-21: Withdrawn
Authors: Manai MM , Thomassin-Piana JJ , Finetti PP , Gammoudi AA , Manai MM , Rahal KK , Birnbaum DD , Boussen HH , Bertucci FF
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Manai MM, Thomassin-Piana JJ, Finetti PP, Gammoudi AA, Manai MM, Rahal KK, Birnbaum DD, Boussen HH, Bertucci FF. 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 P3-10-21.
Abstract P3-11-01: Interaction between molecular subtype and stromal immune infiltration dynamics in breast cancer patients treated with neoadjuvant chemotherapy
Authors: Hamy A-S , Bonsang-Kitzis H , De Croze D , Laas E , Darrigues L , Topciu L , Menet E , Vincent-Salomon A , Lerebours F , Pierga J-Y , Brain E , Feron J-G , Benchimol G , Lam G-T , Laé M , Reyal F
Published: May 2019

Purpose: High levels of tumor-infiltrating lymphocytes (TILs) before neoadjuvant chemotherapy (NAC) are associated with higher pathological complete response (pCR) rates, and better survival in TNBC and HER2-positive breast cancers (BCs). We investigated the value of changes in TIL levels and final TIL levels after treatment, by evaluating lymphocyte infiltration before and after NAC in a real-life BC cohort.

Patients and methods: We assessed stromal TIL levels in 716 pre- and post-treatment matched paired specimens, according to the guidelines of the international TIL working group.

Results: Pre-NAC TIL levels were higher in tumors for which pCR was achieved than in cases of residual disease (33.9% versus 20.3%, p=0.001), in luminal tumors and TNBCs, but not in HER2-positive BCs, (pInteraction =0.001). The association between pre-NAC TIL levels and pCR was non-linear in TNBCs (p=0.005). Mean TIL levels decreased during NAC (pre-NAC TILs: 24.1% versus post-NAC TILs: 13.0%, p<0.001). This decrease was strongly associated with high pCR rates, and TIL level variation was strongly inversely correlated with pre-NAC TIL levels (r=-0.80, p<0.001). Pre-NAC TILs and disease-free survival (DFS) were associated in a non-linear manner (p<0.001). High post-NAC TIL levels were associated with aggressive tumor characteristics and with impaired DFS in HER2-positive BCs (HR=1.04, CI [1.02-1.06], p=0.001), but not in luminal tumors or TNBCs (pInteraction =0.04).

Conclusion: The associations of pre, post-NAC TIL levels with response to treatment and DFS differ between BC subtypes and may deviate from linearity. The characterization of immune subpopulations may improve our understanding of the complex interactions between pre- or post-NAC setting, BC subtype, response to treatment and prognosis.

Citation Format: Hamy A-S, Bonsang-Kitzis H, De Croze D, Laas E, Darrigues L, Topciu L, Menet E, Vincent-Salomon A, Lerebours F, Pierga J-Y, Brain E, Feron J-G, Benchimol G, Lam G-T, Laé M, Reyal F. Interaction between molecular subtype and stromal immune infiltration dynamics in breast cancer patients treated with neoadjuvant chemotherapy [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 P3-11-01.
Abstract P3-11-09: Not presented
Authors: Bownes RJ , Turbull A , Martínez-Pérez C , Sims AH , Oikonomidou O
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Bownes RJ, Turbull A, Martínez-Pérez C, Sims AH, Oikonomidou O. Not presented [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 P3-11-09.
Abstract P3-12-02: Intraoperative radiotherapy outcomes in early-stage breast cancer: A study in elderly Canadian women
Authors: Elmi M , Tigert A , Escallon J , Zagorski B , Leong W , Vranic M , Fyles A , Vitkin A , Cil T , McCready D
Published: May 2019

Objective. Breast-conserving therapy with external beam radiotherapy (EBRT) is currently the standard of care for women with early breast cancer. Our aim was to determine if early-stage breast cancers treated with lumpectomy and primary intraoperative radiotherapy (IORT) have comparable local recurrence rates. This is the first study examining the Canadian experience with IORT.

Methods. Patients who underwent breast-conserving therapy with pre-pathology IORT between 2007- 2017 were retrospectively identified. The primary outcome measure was ipsilateral breast tumor recurrence (IBRT). A time to event analysis was performed; Kaplan-Meier estimates report the fraction of patients living free of recurrence. Secondary outcomes included acute and chronic wound complications.

Results. 106 patients with a median age of 70 (IQR 65-75) were included. Median follow-up was 33 months. The majority of patients had screen-detected (94.3%), estrogen-receptor positive (96.2%), HER2neu negative (93.4%), invasive ductal carcinomas (92.5%). Only 50 (47.6%) were prescribed adjuvant endocrine blockade. IBTR occurred in 5 (4.7%) patients. Five and ten-year local recurrence-free rates were 0.95 and 0.81, respectively. The superficial skin infection rate was 9.4%. Acute symptomatic seromas occurred in 23 (21.7%), while only 10 (9.4%) persisted chronically.

Conclusion. In this cohort of Canadian post-menopausal women treated with breast-conserving surgery and IORT, the IBTR approached 5%. Despite selection of low-risk patients, the local recurrence rate is higher than what is reported in the literature with EBRT. The low rates of prescribed adjuvant systemic therapy may have contributed to this outcome.

Citation Format: Elmi M, Tigert A, Escallon J, Zagorski B, Leong W, Vranic M, Fyles A, Vitkin A, Cil T, McCready D. Intraoperative radiotherapy outcomes in early-stage breast cancer: A study in elderly Canadian 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 P3-12-02.
Abstract P3-12-12: Impact of regional nodal irradiation for breast cancer patients with supraclavicular and/or internal mammary lymph node involvement: A multicenter, retrospective study (KROG 16-14)
Authors: Kim K , Jeong Y , Shin KH , Kim JH , Ahn SD , Kim SS , Suh C-O , Kim YB , Choi DH , Park W , Cha J , Chun M , Lee DS , Lee SY , Kim JH , Park HJ
Published: May 2019

Purpose: To evaluate the treatment outcomes of radiotherapy (RT) for breast cancer with ipsilateral supraclavicular (SCL) and/or internal mammary (IMN) lymph node involvement.

Methods: A total of 353 patients from 11 institutions were included. One hundred and thirty-six patients had SCL involvement, 148 had IMN involvement, and 69 had both. All patients received neoadjvant systemic therapy followed by breast conserving surgery or mastectomy, and postoperative RT to whole breast/chest wall. As for regional lymph node irradiation, SCL RT was given to 344 patients, and IMN RT to 236 patients. The median RT dose was 50.4 Gy.

Results: The median follow-up duration was 61 months (range, 7-173). In-field progression was present in SCL (n=20) and/or IMN (n=7). The 5-year disease-free survival (DFS) and overall survival rates were 57.8% and 75.1%, respectively. On multivariate analysis, both SCL/IMN involvement, number of axillary lymph node ≥4, triple negative subtype, and mastectomy were significant adverse prognosticators for DFS (p = 0.022, 0.001, 0.001, and 0.004, respectively). Regarding the impact of regional nodal irradiation, SCL RT dose ≥54 Gy was not associated with DFS (5-yr rate, 52.9% vs. 50.9%, p = 0.696) in SCL-involved patients, and the receipt of IMN RT was not associated with DFS (5-yr rate, 56.1% vs. 78.1%, p = 0.099) in IMN-involved patients.

Conclusion: Neoadjuvant chemotherapy followed by surgery and postoperative RT achieved an acceptable in-field regional control rate in patients with SCL and/or IMN involvement. However, a higher RT dose to SCL or IMN RT was not associated with the improved DFS in these patients.

Citation Format: Kim K, Jeong Y, Shin KH, Kim JH, Ahn SD, Kim SS, Suh C-O, Kim YB, Choi DH, Park W, Cha J, Chun M, Lee DS, Lee SY, Kim JH, Park HJ. Impact of regional nodal irradiation for breast cancer patients with supraclavicular and/or internal mammary lymph node involvement: A multicenter, retrospective study (KROG 16-14) [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 P3-12-12.
Abstract P3-13-09: Increased mortality with repeat lumpectomy alone after ipsilateral breast tumor recurrence: A propensity-adjusted, population-based SEER analysis
Authors: Su Y , Guo R , Xue J , Chi Y , Wu J
Published: May 2019

Background: The benefit of repeat lumpectomy for ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery (BCS) is currently inconclusive. This issue has become even more important as small and isolated recurrent tumors were frequently diagnosed.

Methods: IBTR patients with definitive surgery were identified in the Surveillance, Epidemiology, and End Results registry between 1973 and 2013. The effect of different IBTR surgeries on overall and cancer-specific mortality was assessed using risk-adjusted Cox proportional hazard regression modeling and stratified propensity score matching analysis (PSMA).

Results: Based on the selection criteria, 5098 patients were recruited. Of those, 4048 (79.4%) women underwent mastectomy and 1050 (20.1%) underwent repeat lumpectomy after IBTR. Patients who received repeat lumpectomy had lower grade (23.7% vs 15% for well-differentiated) and smaller recurrent tumor (47% vs 36.2% for ≤ 1 cm) but earlier recurrence (23.9% vs 11.2% for interval times < 48 months) than those who underwent mastectomy. A minority of each group (24.7% of those undergoing repeat lumpectomy and 3% of the mastectomy group) underwent RT after surgery. In multivariable Cox regression analysis, repeat lumpectomy was associated with increased overall mortality (Hazard ratio (HR) = 1.58, 95% CI = 1.353 to 1.844, P < 0.001) and cancer-specific mortality (HR = 1.721, 95% CI = 1.345 to 2.202, P< 0.001). Similar HRs were derived from the PSMA cohort. However, we found no significant difference in overall mortality for women who underwent repeat lumpectomy followed by RT compared with that for those who underwent mastectomy (P= 0.411). Moreover, IBTR patients with small tumors (≤ 1 cm) who underwent repeat lumpectomy with RT rather than without had similar overall and cancer-specific survival rates to those who underwent mastectomy (P= 0.189 and P= 0.604, respectively).

Conclusions: Our investigation suggests that compared with mastectomy, repeat lumpectomy for IBTR is associated with higher overall and cancer-specific mortality under real-world observational conditions. Furthermore, repeat lumpectomy with RT is equivalent to mastectomy with respect to overall mortality and may influence treatment decision making for patients with small IBTR.

Citation Format: Su Y, Guo R, Xue J, Chi Y, Wu J. Increased mortality with repeat lumpectomy alone after ipsilateral breast tumor recurrence: A propensity-adjusted, population-based SEER analysis [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 P3-13-09.
Abstract P3-13-10: Factors impacting surgical option in patients who achieved complete response in the breast after neoadjuvant systemic therapy
Authors: Kou H-W , Shen S-C , Chen S-C
Published: May 2019

Background:

Neoadjuvant systemic therapy (NST) is the standard treatment for locally advanced breast cancer. Early studies have demonstrated that the rate of breast conservation was significantly increased and NST is now widely applied to operable breast cancer to increase breast conservation rate and to achieve better cosmetic outcome after breast conservative surgery (BCS). For patients who achieved pathologic complete response (pCR), they were perfect candidate for BCS. However, data from prospectively randomized trials have shown that, with the significantly increase of pCR by adding new drugs in the neoadjuvant regimen, BCS rate does not significantly increased. The purpose of current study is to identify factors that have influence on surgical option in patients that have achieved complete response in the breast after NST.

Methods:

From January 2009 to July 2016, 1150 patients with breast cancer received NST in our institute. There were 103 patients achieved complete response (CR) in the breast and were included in current analysis. Medical records were reviewed regarding to individual surgeon, pre-NST clinicopathologic characteristics, and post-NST image findings. Risk factors for mastectomy were assessed by univariate and multivariate analyses.

Results:

Of the 103 patients who achieved CR in the breast, 40 of them (38.8%) received mastectomy. In univariate analysis, physician factor, larger initial tumor size, advanced clinical stages, as well as post-NST image findings including skin change, residual tumor ≥3 cm, short nipple-tumor distance, and residual axillary lymph node(LN) on ultrasound and segmental/diffuse distribution of malignant calcification on mammography were associated with more mastectomy. In multivariate analysis, physician factor (OR=5.192, CI [1.562 – 17.257], p=0.021), residual axillary LN on echography (OR=4.000, CI [1.552 – 10.319], p=0.004), and segmental/diffuse distribution of malignant calcification on mammography (OR=7.500, CI [1.819 – 30.916], p=0.018) were independently related to mastectomy in patients who achieved CR in the breast after NST.

Conclusion:

Physician factor, residual axillary LN and segmental/diffuse malignant calcifications were risk factors for mastectomy in patients who achieved CR in the breast after NST. In addition to embrace current treatment guidelines of surgical management after NST, our data provide valuable additional information to avoid unnecessary mastectomy.

Citation Format: Kou H-W, Shen S-C, Chen S-C. Factors impacting surgical option in patients who achieved complete response in the breast after neoadjuvant systemic therapy [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 P3-13-10.
Abstract P3-13-12: The margin of breast-conserving surgery when ductal carcinoma in situ is present within invasive ductal carcinoma
Authors: Chen J , Ro A , Tan Q-W , Wang Z , Chang HR
Published: May 2019

Objective: The presence of ductal carcinoma in situ (DCIS) in invasive ductal carcinoma (IDC) may increase the rates of positive margins and re-excision. Literature addressing this association is limited. This study aimed to explore the factors that are associated with positive margins and re-excision, as well as to evaluate the influence of positive margins on the survival of patients with breast cancer containing both invasive and in situ ductal carcinoma.

Methods: A retrospective medical chart review of patients diagnosed with DCIS within IDC who underwent BCS at the Revlon/UCLA Breast Center between January 2003 and December 2008 was performed.

Results: Of the 488 eligible patients, 267 patients (53.9%) underwent re-excision. The presence of residual disease upon re-excision was the highest in patients who initially had positive margins involved by both DCIS and IDC. In multivariate analysis, calcifications, tumor size, positive lymph nodes, and the presence of extensive intraductal component (EIC) were significantly associated with initial positive margins, with the latter having the highest hazard ratio (HR, 5.5–5.7, P = 0.000). Tumor size, molecular subtype, and final margin status were associated with disease-free survival. The final margin and regional lymph node status are significant prognosticators for breast cancer-specific survival.

Conclusions: In patients with ductal carcinoma of the breast containing both invasive and in situ components, the rate of initial positive margin after BCS was high and was significantly associated with calcifications, tumor size, regional lymph node status, and the presence of EIC.

Citation Format: Chen J, Ro A, Tan Q-W, Wang Z, Chang HR. The margin of breast-conserving surgery when ductal carcinoma in situ is present within invasive ductal carcinoma [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 P3-13-12.
Abstract P4-01-13: Molecular characterization of circulating tumor DNA in Chinese metastatic breast cancer (mBC) patients
Authors: Yu J , Li H , Zhang S , Wang A , Zhao Z , Liu X-R
Published: May 2019

Background: Circulating tumor DNA (ctDNA) have been increasingly used as a minimal invasive test to detect genomic alterations of cancer patients.

Methods: We performed a retrospective analysis of blood samples from mBC patients (pts) collected at baseline, on-treatment, and disease progression. A highly sensitive, plasma-derived ctDNA-based NGS assay (PredicinePLUS, a comprehensive 180 key cancer gene panel) was used to detect somatic mutations and copy number variations in ctDNA with an in-house propriety algorithm.

Results: In this study, we evaluated 162 blood samples from 109 mBC pts who underwent systematic therapy at Beijing Cancer Hospital with approval from Research Ethics Committee. 129 samples from 92 pts passed NGS quality check, and were included in the analysis. Among these pts, the percent of HR+, HER2+ and Triple-Negative pts is 36.8%, 29.5% and 31.5%, respectively. About 86% samples contain somatic mutations and/or copy number variations. Collectively, 372 somatic mutations (SNV and Indels) were detected on 76 genes, among which TP53 (44.2%), PIK3CA (25.3%), BRCA2(10.5%) and ATM (10.5%) were frequently altered with frequency varying across different subtypes. ESR1 hotspot mutations ((D538G and Y537S/N/C) were also detected in a subset of HR+ patients. Copy number gain or loss was detected on 32 genes, including amplification of ERBB2, PIK3CA, FGFR1 and deletion of CDKN2A, ATM, RB1 etc. Importantly, ERBB2 copy number amplifications were only detected in HER2 IHC positive cases for base-line samples, leading to 68% sensitivity and 100% specificity. Interestingly, ctDNA yield increased as disease progressed, suggesting ctDNA yield may serve as a potential biomarker for predicting treatment response and monitoring disease progression. Additional genomic alterations that change dynamically along with the course of treatment or associate with drug response and/or resistance were also identified.

Conclusions: This study demonstrated ctDNA-based genomic analysis was highly sensitive and specific in detecting various genomic alterations, consistent with other published studies. It also suggests that HER2 copy number amplification could be robustly assessed in a non-invasive manner.

Citation Format: Yu J, Li H, Zhang S, Wang A, Zhao Z, Liu X-R. Molecular characterization of circulating tumor DNA in Chinese metastatic breast cancer (mBC) 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 P4-01-13.
Abstract P4-01-24: S100A11 is a diagnostic marker and promotes cancer progression for luminal breast cancer
Authors: Kwong A , Wang J , Chen J , Siu MT , Chuek I , Shin V
Published: May 2019

Background: S100A11, also known as calgizzarin, is a member of S100 calcium-binding protein family and is upregulated in various cancers including lung cancer, renal cell cancer, ovarian cancer and pancreatic cancer. Many studies have shown that S100A11 is related to cancer progression. However, the function of S100A11 in breast cancer remains largely unknown. In the present study, we aim to investigate the underlying mechanism(s) of S100A11 in cancer cell proliferation, invasion, migration, and evaluate the clinical association with breast cancer.

Methods: The mRNA expression level of S100A11 in plasma samples from breast cancer patients and normal control individuals was detected with quantitative real-time PCR. Knockdown of S100A11 using small interfering RNA (siRNA) in luminal breast cancer cells (MCF-7 and T-47D) were used to study the biological function of S100A11 for the progression of breast cancer. Cell proliferation ability was analysed with MTT assay and colony formation assay. Cell invasion ability was analysed with transwell invasion assay. Cell migration ability was detected by wound healing assay. Cell cycle distribution and apoptosis were determined by flow cytometry.

Results: The mRNA expression level of S100A11 was significantly increased in the plasma samples obtained from 182 breast cancer patients compared with 115 normal control individuals, and the area under curve was 0.83. In particular, higher expression was associated with luminal breast cancer subtype as well as respective cell lines. S100A11 siRNA effectively inhibited the proliferation, invasion, and migration abilities of MCF-7 and T-47D cells. Knockdown of S100A11 caused cell cycle G1 arrest and induced apoptosis. Silencing of S100A11 decreased the mRNA and protein expression levels of cyclin D1 and NF-κB p50 whereas increased the expression level of E-cadherin in MCF-7 and T-47D cells.

Conclusion: These results suggest that S100A11 is upregulated in breast cancer and promoted cell proliferation, invasion and migration in MCF-7 and T-47D cells through the upregulation of NF-κB p50 and cyclin D1. Thus, S100A11 may be a potential diagnostic marker for luminal breast cancer subtype and also a therapeutic target for breast cancer.

Citation Format: Kwong A, Wang J, Chen J, Siu MT, Chuek I, Shin V. S100A11 is a diagnostic marker and promotes cancer progression for luminal 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 P4-01-24.
Abstract P4-03-05: Not presented
Authors: Carraro DM , Palmero EI , Galvao HC , Berra CM , Brianese RC , Torrezan GT , da Cruz Formiga MN , de Lima FT , Fernandes GC , de Paula AE , Michelli RD , Gutierrez Barrera AM , Arun BK
Published: May 2019

This abstract was not presented at the conference.

Citation Format: Carraro DM, Palmero EI, Galvao HC, Berra CM, Brianese RC, Torrezan GT, da Cruz Formiga MN, de Lima FT, Fernandes GC, de Paula AE, Michelli RD, Gutierrez Barrera AM, Arun BK. Not presented [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 P4-03-05.
Abstract P4-03-08: Analyzing the clinical actionability of germline CYP2D6 polymorphism in Chinese breast cancer population
Authors: Huang L , Cao A
Published: May 2019

Background:Tamoxifen is effective for endocrine-responsive breast cancer as adjuvant therapy. CYP2D6 enzyme metabolizes tamoxifen to clinically active metabolites, while CYP2D6 polymorphisms may adversely affect tamoxifen efficacy by some retrospective clinical evidence. This study was carried out to estimate genotype frequencies of common variants of CYP2D6 in Chinese population. The relationship between prescription of selective estrogen receptor modulators (SERMs) and CYP2D6 polymorphism was also analyzed.

Methods: This was a retrospective research of early-stage patients who underwent surgical treatment at Fudan University Shanghai Cancer Center with ER+ and/or PR+ breast cancer. Genomic DNA was extracted from peripheral blood, which was used for genotyping CYP2D6*10 (C100T) single-nucleotide polymorphisms by polymerase chain reaction-based methods.

Results: A total of 312 patients with primary breast cancer were identified. More than 90.0% patients were in premenopausal status. The allele frequence of CYP2D6*10 in the Chinese population was 54.3%. The genotype frequencies of CYP2D6*10 were 20.5%, 50.3%, 29.2%, for wild-type, heterozygous and homozygous type respectively. We also found this SNP had no significant correlation with clinical characteristics. 145 patients were continuing endocrine treatment in first 5 years. 34.5% patients received CYP2D6 polymorphism test before the prescription of SERMs. The results significantly effected the choice of SERMs. Only 6.2% homozygous type patients took tamoxifen, 45.5% heterozygous patients chose tamoxifen, while 75.0% for wild type. 65.5% patients received CYP2D6 polymorphism test during the treatment of tamoxifen. 63.9% homozygous type patients switched to Toremifene, while 18.9% heterozygous patients changed the endocrine treatment.

Conclusions: The results showed that the frequence of CYP2D6*10 allele was high and nearly 30% Chinese breast cancer population were intermediate metabolizer for tamoxifen. The cyp2d6 polymorphism would influence prescription of SERM in premenopausal breast cancer patients. Patients with homozygous types should take other endocrine treatment instead of tamoxifen, which need more evidence of prospective clinical trials.

Citation Format: Huang L, Cao A. Analyzing the clinical actionability of germline CYP2D6 polymorphism in Chinese breast cancer population [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 P4-03-08.
Abstract P4-04-08: Genomic profiling of 304 treatment-naïve Chinese breast cancer patients: A comparison of Chinese and TCGA cohorts
Authors: Liao N , Zhang G , Wang Y , Guo L , Cao L , Zhang Z , Balch CM , Meric-Bernstam F
Published: May 2019

Background: The complexity of BC at the clinical, morphological and molecular level has been well recognized. Molecular profiling, which reveals the intrinsic biology among subtypes, has significantly advanced the management of this disease. However, previous studies have provided very limited molecular data on Chinese breast cancer patients.

Methods: We performed targeted sequencing using a panel consisting of 36 BC related genes to interrogate the genomic landscape of 304 consecutive treatment-naïve Chinese BC patients and compared our results to the TCGA data set.

Results: Comparing to TCGA, our cohort had significantly fewer patients with triple negative breast cancer (8.2% vs 15.5% p=0.002). The most prominent genomic difference was our cohort had significantly higher TP53mutation frequency in HR+/HER2- and HR+/HER2+ groups. The composition of TP53 mutations also differed significantly between two cohorts in HR+/HER2- group, with TCGA cohort having missense mutation as the predominant mutation; whereas, in our cohort, nonsense and frameshift mutations were predominant. We classified the most populated and diverse group of HR+/HER2- cancer into 4 subgroups based on molecular signature. The clinical significance of this proposed classification was confirmed by differences in overall survival using data from the TCGA.

Conclusions:We identified distinctive genomic patterns associated with Chinese breast cancer patients compared to TCGA data, suggesting the importance of mutation-based stratification according to ethnic status. To the best of our knowledge, this is one of the largest study of Chinese BC patients that interrogated the spectrum of mutational events and correlated these molecular signatures with clinical outcomes.

This study was supported by funding from National Natural Science Foundation of China (Grant No. 81602645), Guangdong Provincial Natural Science Foundation (Grant No. 2016A030313768) and Research Funds from Guangzhou Science and Technology Bureau (Grant No. 201707010418 and 201804010430).

Citation Format: Liao N, Zhang G, Wang Y, Guo L, Cao L, Zhang Z, Balch CM, Meric-Bernstam F. Genomic profiling of 304 treatment-naïve Chinese breast cancer patients: A comparison of Chinese and TCGA cohorts [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 P4-04-08.
Abstract P4-04-10: Genomic profiling of multifocal breast cancer reveals inter-lesion heterogeneity
Authors: Ahn S , Kim HJ , Kang E , Kim E-K , Kim SH , Kim JH , Kim IA , Park SY
Published: May 2019

Introduction: Multifocal breast cancers are common, and tend to show more aggressive clinical features than unifocal breast cancers. While each foci of multifocal breast cancers with similar histology shares the same hormone and ERBB2 receptor status in most cases, substantial genomic differences among lesions have been reported. We aimed to investigate the potential genomic differences between multifocal breast cancer lesions.

Materials and methods: Twenty-one patients with multifocal breast cancer documented in the resection specimen were included. We selected two lesions with the same histology from each of these 21 patients. Capture-based targeted next generation sequencing was performed using a cancer gene panel consisting of 170 genes for single nucleotide variants (SNV) and small insertions/deletions (Indel), and copy number alterations.

Results: The most frequent mutation was TP53 (38.1%), followed by PIK3CA (28.6%). Pathogenic mutations (SNV and Indel) were detected in 13 of 21 patients, of whom 11 shared oncogenic variants in the two lesions. The remaining two patients had different mutation results in TP53 and PIK3CA, respectively. Genomic heterogeneity of copy number alteration was observed in 6 (28.6%) of 21 patients, including difference of FGFR1 status in two patients and difference of FGFR2 status in one patient.

Conclusion: Despite similar histologic features of multifocal tumors, genomic inter-lesion heterogeneity was identified in about one-fourth of patients. The spatial genomic heterogeneity in multifocal breast cancers needs to be considered in representative sampling and molecular tests for personalized medicine.

Citation Format: Ahn S, Kim HJ, Kang E, Kim E-K, Kim SH, Kim JH, Kim IA, Park SY. Genomic profiling of multifocal breast cancer reveals inter-lesion heterogeneity [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 P4-04-10.
Abstract P4-04-11: A small amount of primary breast cancer shows high tumor mutation burden that may benefit from immune checkpoint inhibitor therapy
Authors: Wang J , Chen W , Jiang Z , Lin X , Qin T , Yang X , Liu T , Hu H , Li Z , Xie D , Yao H , Song E
Published: May 2019

Background: Targeted therapy using immune checkpoint inhibitors (ICIs) is a major breakthrough in cancer treatment in the last decade. ICIs like PD1 or PD-L1 antibodies have been shown to be quite effective in cancer like melanoma. However, in most other tumor types including breast cancer, the situation is not as optimistic. Only a small percentage of those patients respond to ICIs therapy. This highlights the importance of identifying biomarkers to predict which patients may benefit from such treatment. Tumor Mutation Burden (TMB) has been shown to be a sensitive marker for ICI treatment. This study is to investigate whether TBM could be used as a biomarker for breast cancer treatment.

Methods: We reviewed next generation sequencing studies of breast cancer. Two such studies with raw data provided were included in our analysis. One study entitled METABRIC performed targeted sequencing of 173 cancer-related genes in around 2500 primary breast cancer tissues. The other study was from TCGA breast cancer project, which performed Whole Exome Sequencing (WES) of around 1000 primary breast cancer samples. Mutation data were downloaded from public data deposit. The number of mutations per sample was calculated. TBM was calculated by divide the coverage in million base pair from that of the total mutation counts.

Results: In METABRIC study, 17272 mutations were identified in 2369 samples, with a median of 7 mutations per sample (95% CI: 6 ˜ 7). The median TMB of METABRIC dataset was 5.8 SNVs/Mb (95% CI: 5 ˜ 5.8). Totally 30 out 2369 (1.3%) samples had a TMB equal or large than 20 SNVs/Mb. In another cohort from TCGA breast cancer study using WES technology, 90172 mutations were identified in 977 samples, with a median of 44 mutations per sample (95% CI: 39 ˜ 50). The median TMB was 1 SNVs/Mb (95% CI: 0.9 ˜ 1.1). Totally 13 out 977 (1.3%) samples had a TMB equal or large than 20 SNVs/Mb.

Conclusions: Breast cancer shows middle to low mutation burden compared to other cancer types. Around 1.3% of breast cancer has quite high TMB of at least 20 SNVs/Mb, which may be qualified for immune checkpoint inhibitors therapy. Our study indicates that TMB may be incorporated as a standard test for late stage breast cancer patients in the clinical practice.

Keywords: Breast cancer, Tumor Mutation Burden, Whole exome sequencing, Targeted sequencing, Immune checkpoint

Citation Format: Wang J, Chen W, Jiang Z, Lin X, Qin T, Yang X, Liu T, Hu H, Li Z, Xie D, Yao H, Song E. A small amount of primary breast cancer shows high tumor mutation burden that may benefit from immune checkpoint inhibitor therapy [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 P4-04-11.
Abstract P4-06-15: Role of B lymphocytes and B cell-produced IL-27 in breast cancer progression and drug resistance
Authors: Yan H , Viswanadhapalli S , Fernandez M , Rivera C , Sareddy G , Casali P , Vadlamudi R
Published: May 2019

How host immune elements, particularly B cells, are hijacked to promote breast cancer (BCa) tumor progression and acquisition of resistance to current endocrine therapies remain largely unclear. Prompted by our recent findings that B cells are a major source of cytokine IL-27 (the heterodimer of IL-27p28 and EBI3), which regulates many immune functions as both a pro-inflammatory and anti-inflammatory cytokine, as well as the high expression of IL-27 receptor genes in the breast, elevated circulating IL-27 in BCa patients and the association of increased IL-27p28 expression with reduced survival in BCa patients overall and ER+ BCa patients after endocrine therapies, here we hypothesize that B cells promote BCa tumor progression and drug resistance and do so by producing IL-27. In C57 mice transplanted with ERa+ E0771 syngeneic medullary breast adenocarcinoma cells, deficiency in B cells in mMT mice resulted in virtually abolished tumor growth, resulting from significantly high tumor cell death. Remarkably, in residual tumors developed in mMT mice after transplantation with a higher load of E0771 cells, B cells, which were absent in the blood and lymph nodes, were accumulated within tumors – at an even higher frequency than that in wildtype C57 mice – and expressed IL-27. Further, like class-switching B cells that respond to IL-27 produced by neighboring B cells to express an IFNg-induced gene signature in the secondary lymphoid organ during the antibody response, a distinct population of tumor-infiltrating B cells expressed high levels of PD-L1, which could be induced by IL-27 in many immune cell types, including B cells, and several cancer cell types. Finally, IL-27 promoted the growth MCF-7 human BCa cells in the presence of tamoxifen in vitro, consistent with a role of B cell-produced IL-27 in the acquisition of drug resistance by BCa. These, together with the delayed tumor growth in mixed bone marrow chimeric mice with B cell-specific deficiency in IL-27 production, outline a potential role of B cell-produced IL-27 in BCa progression and drug resistance through both BCa cell-intrinsic mechanisms and induction of PD-L1+ B regulatory cells that participate in the immune checkpoint in BCa.

Citation Format: Yan H, Viswanadhapalli S, Fernandez M, Rivera C, Sareddy G, Casali P, Vadlamudi R. Role of B lymphocytes and B cell-produced IL-27 in breast cancer progression and drug 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 P4-06-15.
Abstract P4-06-18: Withdrawn
Authors: Dunbier AK , Hazlett J , Niemi G , Kemp R
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Dunbier AK, Hazlett J, Niemi G, Kemp R. 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 P4-06-18.
Abstract P4-07-11: Investigating the activity of ESR1 allosteric compounds in ER+ breast cancer
Authors: Uwimana A , Tiong Yip CL , Das R , Cheng Q , Meredith E , Gaither AL
Published: May 2019

Breast cancer (BCa) is the most frequently diagnosed cancer in women worldwide. Approximately 80% of breast cancer is estrogen receptor positive (ER+) with 74% demonstrating high expression of estrogen receptor alpha (). Thus, current endocrine therapies such as selective estrogen receptor degraders (i.e.- Fulvestrant) or selective estrogen receptor modulators (i.e-Tamoxifen) are involved modulation of ER signaling. However, most patients develop resistance to these drugs, and disease progression is common resulting in metastatic disease. Therefore, targeting alternative sites on the surface of has been proposed as an effective therapy to directly block its activity. In the present study, we investigated putative AF2 compounds that can bind to AF2 allosteric sites and inhibit complex formation and transcription of targetgenes. In the present study, we characterized a series of allosteric compounds using breast cancer cellular assays. MCF7 parental cells were treated with a series of putative allosteric compounds in a seven day CTG cell proliferation assay, and the compound ERX-11 was found to exhibit anti-proliferative activity. Genomic RNA was isolated after overnight treatment with ERX-11 to investigate compounds treatment on the expression of key ER pathway transcription factors via real time PCR. The degradation effect on nuclear ER and cytoplasmic ER after treatment with ERX-11 were assessed via western blots. We successfully characterized a series of putative allosteric compounds with ERX-11 being the only compound that exhibited anti-proliferative activity in both MCF7 parental and LSZ resistant cells. ERX-11 inhibited the activation of ER transcription gene and degradation of nuclear ER. These findings show promising effects of ERX-11 to block the AF2 sites on the binding domain of ERα with potential therapeutics for ER+ breast cancer.

Citation Format: Uwimana A, Tiong Yip CL, Das R, Cheng Q, Meredith E, Gaither AL. Investigating the activity of ESR1 allosteric compounds in ER+ 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 P4-07-11.
Abstract P4-08-14: Invasive micropapillary carcinoma had no difference in prognosis compared with invasive ductal carcinoma: A propensity-matched analysis
Authors: Hao S , Zhao Y-Y , Peng J-J , Yang W-T , Ren F , Yu K-D , Shao Z-M
Published: May 2019

Background: Invasive micropapillary carcinoma (IMPC) is a rare histopathological variant of breast carcinoma and usually performs poor clinical characteristics, such as high tendency of lymph nodes metastases. But whether it has worse prognosis than invasive ductal carcinoma (IDC) is still controversial nowadays. We conducted this retrospective study to figure out the prognostic difference between IMPC and IDC, then guide therapy of IMPC ultimately.

Methods: In this study, we analyzed 327 cases of IMPC patients and 4979 cases of IDC who underwent primary resection in our institution during 2008 to 2012. By using propensity score matching, two groups were matched at a ratio of 1:1 by age, tumor size, nodal status, hormone and HER2 status to demonstrate the difference of prognosis assessed by Kaplan-Meier estimates and Cox regression analysis.

Result: After a mean follow-up of 52 months, we established the IMPC group and figured out 324 IDC patients from the control group by propensity score matching (3 IMPC patients were canceled because of data missing). The result of survival analysis indicated that women diagnosed with IMPC had no significant reduced overall survival (OS) (p = 0.752) and disease-free survival (DFS) (p = 0.578) compared with women with IDC. Multivariate Cox regression analysis revealed that IMPC was not found as an independent prognostic factor for DFS (hazard ratio [HR] = 0.858; 95% confidential interval [CI], 0.419-1.757) or OS (HR = 0.720; 95%CI, 0.353-1.469).

Conclusion: The consequence of survival analysis manifested that there was no statistically significant difference between 2 groups, and elucidated proactive or radical clinical therapy was unnecessary.

Citation Format: Hao S, Zhao Y-Y, Peng J-J, Yang W-T, Ren F, Yu K-D, Shao Z-M. Invasive micropapillary carcinoma had no difference in prognosis compared with invasive ductal carcinoma: A propensity-matched analysis [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 P4-08-14.
Abstract P4-08-19: Progression-free survival or time to progression in comparative clinical trials of metastatic breast cancer as a potential surrogate for overall survival: A systematic review of 49 trials focusing on breast cancer subtype
Authors: Tsukioki T , Taira N , Sakamaki K , Suzuki Y , Kajiwara Y , Hatono M , Takahashi Y , Kawata K , Kochi M , Iwamoto T , Ikeda H , Shien T , Doihara H
Published: May 2019

Background: Overall survival (OS) is the established endpoint to evaluate the effects of drug treatment in comparative clinical trials of metastatic breast cancer. But assessing OS requires long follow-up periods and large sample size, which raise costs and create long delays in the drug approval process. Progression-free survival (PFS) or time to progression (TTP) is considered as a surrogate for OS and is often used as an alternative to OS. In some cancers the two endpoints are highly correlated, but in others they are not. Furthermore, the effect of breast cancer (BC) subtypes on the surrogacy of PFS/TTP for OS has not been completely defined.

Method: A systematic literature review of randomized control trials was conducted to identify studies that reported both the hazard ratio (HR) of PFS/TTP and OS for BC subtypes {i.e. estrogen receptor (ER) positive, HER2 positive, and triple negative (TN)}. The correlation between the HR of PFS/TTP and OS was evaluated using weighted Spearman's rank correlation.

Results: A total of 49 trials (34 phase III trials and 15 phase II trials) were selected for analysis. Among these trials, there were 8 comparison trials between one chemotherapy and another chemotherapy regimen, 18 comparison trials between chemotherapy and chemotherapy plus molecularly-targeted therapy, 9 comparison trials between one endocrine therapy and another endocrine therapy, and 5 comparison trials between endocrine therapy and endocrine therapy plus molecularly-targeted therapy. There were 17 trials reporting the HR of PFS/TTP and OS for ER positive, 16 trials for HER2 positive, and 9 trials for TN BC. Weighted Spearman's rank correlation revealed that coefficient between the HR of PFS/TTP and OS was 0.721(p<.0001) for all trials, 0.873(p< .0001) for ER positive, 0.642(p=0.0055) for HER2 positive, and 0.615(p=0.078)for TN BC.

Conclusion: There was a strong correlation between the HR of PFS/TTP and OS for ER positive BC, and a weak correlation between the HR of PFS/TTP and OS for HER2 positive and TN BC. The validity of using PFS/TTP as an OS surrogate marker was shown for metastatic BC, especially for ER positive BC.

Citation Format: Tsukioki T, Taira N, Sakamaki K, Suzuki Y, Kajiwara Y, Hatono M, Takahashi Y, Kawata K, Kochi M, Iwamoto T, Ikeda H, Shien T, Doihara H. Progression-free survival or time to progression in comparative clinical trials of metastatic breast cancer as a potential surrogate for overall survival: A systematic review of 49 trials focusing on breast cancer subtype [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 P4-08-19.