bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract GS3-03: Effects of prolonging adjuvant aromatase inhibitor therapy beyond five years on recurrence and cause-specific mortality: An EBCTCG meta-analysis of individual patient data from 12 randomised trials including 24,912 women
Authors: Gray R ,   Early Breast Cancer Trialists' Collaborative Group
Published: May 2019

Effects of prolonging adjuvant aromatase inhibitor therapy beyond five years on recurrence and cause-specific mortality: an EBCTCG meta-analysis of individual patient data from 12 randomised trials including 24,912 women

Background: Five years of endocrine therapy with tamoxifen and/or an aromatase inhibitor is highly effective in reducing the risk of recurrence but a substantial risk remains after treatment discontinuation. Continuing treatment with an aromatase inhibitor may mitigate this risk.

Methods: We sought individual patient data for meta-analysis from 12 randomised trials that compared 3-5 years of aromatase inhibitor versus no further treatment after five or more years of endocrine therapy. Primary outcomes were recurrence, and breast cancer mortality. Predefined subgroup comparisons were or prior endocrine therapy (tamoxifen alone, tamoxifen then AI, AI alone), site of recurrence (distant, local, contralateral), age, nodal status, tumour size, grade, and period of follow-up (yrs 0-1, 2-5, 5-9, 10+). Five trials randomised 2-3 years prior to treatment divergence and the primary analyses included only women who were recurrence and second primary cancer free and still alive at the point of treatment divergence.

Results: Data have so far been received on 7,488 women (100% of those randomised) in trials of extended AI following tamoxifen alone, 10,796 women (82% 0f 13,192 randomised) following prior tamoxifen then AI, and 959 (23% of 4,229 randomised) following AI alone. Preliminary analyses including 1,617 breast cancer recurrences and 854 breast cancer deaths confirm a 35% reduction in recurrence with extended AI following tamoxifen alone but suggest a more moderate reduction after prior AI therapy. Data from two trials (NSABP B-42 & N-SAS BC 05) contributing ˜5666 women should be available before SABCS to allow definitive analyses.

Conclusion: This meta-analysis will provide the most reliable possible summary of the available evidence to inform clinicians on the efficacy of extending AI therapy compared to stopping AI after about 5 years of endocrine therapy in preventing disease recurrence and death from breast cancer, both overall and in different categories of women.

Citation Format: Gray R, Early Breast Cancer Trialists' Collaborative Group. Effects of prolonging adjuvant aromatase inhibitor therapy beyond five years on recurrence and cause-specific mortality: An EBCTCG meta-analysis of individual patient data from 12 randomised trials including 24,912 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 GS3-03.
Abstract GS6-06: Local therapy and quality of life outcomes in young women with breast cancer
Authors: Dominici LS , Hu J , King TA , Ruddy KJ , Tamimi RM , Peppercorn J , Schapira L , Borges VF , Come SE , Warner E , Partridge AH , Rosenberg SM
Published: May 2019

Background: Increasing rates of mastectomy, primarily bilateral mastectomy (BMx), have been most dramatic in young women with breast cancer (BC). Impact on long-term quality of life (QOL) is largely unknown.

Methods: Between 10/2016-11/2017, we administered the BREAST-Q, a validated patient-reported outcomes measure, to women dx with BC at age ≤40 in a large prospective cohort study. Demographic and treatment information was obtained by surveys and chart review. Mean BREAST-Q scores for each domain (breast satisfaction, physical, psychosocial, and sexual) were compared by surgery types; higher BREAST-Q scores (range: 0-100) indicate better QOL. Linear regression was used to identify predictors of BREAST-Q domain scores.

Results: 581 women with stage 0-3 BC completed the BREAST-Q a median of 5.8 years from dx. Median age at dx was 37 (range: 26-40) years; 86% had stage 0, 1 or 2 disease; 28% had breast-conserving surgery (BCS); 72% had mastectomy (Mx), among whom 72% underwent BMx and 89% had reconstruction. Mean BREAST-Q scores (unadjusted) for breast satisfaction, psychosocial, and sexual well-being were lower for patients having unilateral mastectomy (UMx) or BMx compared to BCS; physical function was similar among groups. In multivariate analysis, lower BREAST-Q psychosocial scores were associated with radiation and Mx (UMx or BMx). Lower sexual well-being scores were also associated with Mx. Lower satisfaction with breast scores following radiation were of a clinically significant magnitude (β -8.1 95% CI -11.9- -4.3, p-value 0.03). Lower scores for physical well-being were seen for patients reporting lymphedema and higher for those who had undergone surgery more than 5 years prior. Lower scores across all 4 domains were associated with reported financial distress.

BREAST-Q domain mean scores (SD) BMxUMxBCSp-valueBreast satisfaction60.3 (18.9)59.5 (21.3)65.9 (20.7)0.008Physical well-being78.6 (14.9)79.7 (15.1)78.9 (15.5)0.8Psychosocial well-being68.1 (20.8)70.5 (21.2)76.1 (20.5)<0.001Sexual well-being48.6 (21.3)53.2 (21.7)57.5 (18.7)<0.001SD Standard deviation

Conclusion: Local therapy in young breast cancer survivors may have a persistent impact on their breast satisfaction, psychosocial, and sexual outcomes, with particular effects from UMx or BMx. Socio-economic stressors also appear to play a role. When counseling young women about their surgical decisions, knowledge of potential long-term QOL impact is of critical importance.

Citation Format: Dominici LS, Hu J, King TA, Ruddy KJ, Tamimi RM, Peppercorn J, Schapira L, Borges VF, Come SE, Warner E, Partridge AH, Rosenberg SM. Local therapy and quality of life outcomes in young women with 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 GS6-06.
Abstract MS1-2: Deep learning systems for reading mammograms and breast tomosynthesis
Authors: Karssemeijer N
Published: May 2019

Recent breakthroughs in machine learning resulted in powerful techniques that allow reseachers to accelerate development of automated systems for interpreting medical images. With the use of deep learning and very large training databases, limitations of conventional computer aided detection (CAD) systems, which are widely used in mammography, can be overcome. It is expected that in the coming years algorithms will become more accurate that human readers for interpreting screening mammograms. This will enable physicians to substantially increase quality of mammography. It also will reduce the need for human resources, which is important because many countries face challenges with recruitment of mammographers. In the presentation, experimental study results will be presented which illustrate that deep learning systems are approaching the level of performance of human readers and that there is potential to increase the quality of automated interpretation of mammograms and breast tomosynthesis beyond to the level of experts

Citation Format: Karssemeijer N. Deep learning systems for reading mammograms and breast tomosynthesis [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 MS1-2.
Abstract MS1-3: Artificial intelligence to optimize the accuracy and predictiveness of breast cancer pathology
Authors: Beck A
Published: May 2019

Pathologic analysis of patient tissue specimens plays a central role in breast oncology. Recent advances in artificial intelligence and computer vision offer tremendous potential for discovering new pathologic mechanisms of cancer treatment response and identifying new diagnostics for matching patients and therapies. We will discuss these new advances and their potential for accelerating progress in the diagnosis and treatment of breast cancer.

Citation Format: Beck A. Artificial intelligence to optimize the accuracy and predictiveness of breast cancer pathology [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 MS1-3.
Abstract OT1-01-01: The NEO-LET-EXE-trial: An intra-patient cross-over trial to explore the "lack of cross-resistance" between steroidal and non-steroidal aromatase inhibitors
Authors: Bahrami N , Sauer T , Loeng M , Gravdehaug B , Engebretsen SS , Aljabri B , Bemanian V , Lindstrøm JC , Lüders T , Kristensen VN , Geisler J
Published: May 2019

Background. The aromatase inhibitor letrozole and the aromatase inactivator exemestane currently belong to the most widely used antihormonal drugs for breast cancer worldwide. Both compounds are strongly suppressing estradiol levels in postmenopausal patients with breast cancer. However, in the metastatic setting, these drugs may be used after another, causing new responses in selected patients following switching to the alternative drug after progressing on the first choice. This well-known “lack of cross resistance” has been recognized for some time and is documented by several trials. However, the precise explanation for this clinical observation is still unknown. The solution may potentially lead us to a novel strategy to treat hormone-sensitive breast cancer.

Trial design. NEO-LET-EXE is a neoadjuvant, randomized, open-label, intra-patient cross-over trial .

Eligibility criteria. Postmenopausal patients suffering from estrogen receptor (ER) positive (>50%), HER-2 negative, locally advanced breast cancer, suitable for neoadjuvant/presurgical antihormonal therapy, may be enrolled. Age: 18+ (no upper limit).

Specific aims. To explain the phenomenon of a lack of cross-resistance between steroidal and non-steroidal aromatase inhibitors in vivo. Sequential tumor biopsies and blood samples, obtained at baseline and following 2 months of therapy with each drug given in sequence, will be used to perform a comprehensive exploration of the consequences of each drug therapy. The influence on plasma and tissue steroids (estrogens, androgens, etc.) will be compared. In addition, whole genome sequencing, whole exome sequencing, epigenetics, proteomics and plasma analysis (cytokines, tumor DNA fragments, etc.) will be performed.

Statistical methods. Data will be analyzed using mixed effects models.

Present accrural and target accrural. 49 out of planned 100 patients have been enrolled so far. The last patient is expected to enter the trial in Q4 2019.

Citation Format: Bahrami N, Sauer T, Loeng M, Gravdehaug B, Engebretsen SS, Aljabri B, Bemanian V, Lindstrøm JC, Lüders T, Kristensen VN, Geisler J. The NEO-LET-EXE-trial: An intra-patient cross-over trial to explore the "lack of cross-resistance" between steroidal and non-steroidal aromatase inhibitors [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 OT1-01-01.
Abstract OT1-02-01: Phase I trial of bicalutamide and ribociclib in androgen receptor-positive triple negative breast cancer
Authors: Sharifi M , Wisinski KB , Burkard ME , Tevaarwerk AJ , Tamkus D , Chan N , Truica C , Danciu O , Hoskins K , O'Regan RM
Published: May 2019

Background: To date, the use of anti-androgens in the subset of triple negative breast cancers (TNBC) that express androgen receptor (AR) has shown modest response rates, indicating anti-androgen-resistance in the majority of these tumors. Based on data that Cyclin D kinase (CDK) inhibitors reverse resistance to anti-androgens in prostate cancer cell lines, we hypothesize that the use of CDK inhibition may enhance the activity of anti-androgens in AR-positive TNBC.

Methods: Key eligibility include: patients with centrally confirmed AR-positive TNBC, defined as AR expression >0%; 0 to 1 line of prior therapy for metastatic disease; and measurable disease. Patients are treated with bicalutamide 150mg orally once daily plus ribociclib at one of 3 dose levels (see table).

Table 1Dose levelBicalutamideRibociclib1150mg orally once daily (D1 to 28)400mg daily (D1 to 21)2150mg orally once daily (D1 to 28)400mg daily (D1 to 28)3150mg orally once daily (D1 to 28)600mg daily (D1 to 21)

Results: AR expression was positive by trial criteria in 74% of screened patients. Three patients have been accrued at each dose level. Median age is 56 and 6 and 3 patients were treated in first and second-line settings, respectively. Median AR expression was 50% (range 5 to 75%). Toxicity data is available for 6-patients treated on dose levels 1 and 2. No dose-limiting toxicities were noted. As anticipated with ribociclib, the most common toxicity is neutropenia (1 patient grade 4 and 2 patients grade 3). Two patients experienced grade 3 hypertension and 1 experienced grade 3 lymphopenia. Grade 2 or lower toxicities included fatigue, nausea, hyperglycemia and mucositis. One patient experienced grade 1 QT interval prolongation.

Conclusion: The combination of bicalutamide and ribociclib is tolerable without unexpected toxicities. Data on the 3-patients treated at dose level 3 and dose expansion will be included. Phase 2 dosing schedule will be decided based on phase 1 results.

Citation Format: Sharifi M, Wisinski KB, Burkard ME, Tevaarwerk AJ, Tamkus D, Chan N, Truica C, Danciu O, Hoskins K, O'Regan RM. Phase I trial of bicalutamide and ribociclib in androgen receptor-positive triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-02-01.
Abstract OT1-05-03: Efficacy and safety of scalp cooling device for prevention of alopecia in patients with breast cancer
Authors: Kodera A , Ogura K , Hattori A , Yukawa H , Sakaguchi S , Matsuoka A , Tanaka N , Kamimura M , Jibiki N , Naritaka Y , Hirano A
Published: May 2019

Background

Chemotherapy for breast cancer causes alopecia as a side effect. Some patients refuse chemotherapy because of alopecia, resulting in the omission of a standard therapy. It is believed that a scalp cooling device can prevent alopecia by promoting vasoconstriction of the scalp and reducing exposure of the hair root cells to anticancer agents. There are phenotypic differences of the efficacy of a scalp cooling device for alopecia. In fact, a Dutch scalp cooling registry reported that the success rate of scalp cooling was 51% in European women and 33% in Asian women. Therefore, we aimed to investigate the efficacy of scalp cooling device for chemotherapy-induced alopecia among Asian women with breast cancer.

Trial design

This is a phase II trialto evaluate the efficacy and safety of scalp cooling device for risk reduction of alopecia in women with stage I/II/III breast cancer treated with adjuvant/neoadjuvant chemotherapy in a single institute.

Eligibility criteria

Women diagnosed with Stage I to III breast cancer who are scheduled to receive preoperative or postoperative adjuvant chemotherapy containing anthracycline and/or taxanes are enrolled. Patients who have blood malignancies (leukemia, non-Hodgkin lymphoma, other systemic lymphoma), and cold allergy, are excluded.

Specific aims

The primary endpoint is the proportion of patients with Common Terminology Criteria for Adverse Events (CTCAE) grade 0-1 alopecia after the completion of all cycles of chemotherapy (success rate). Secondary endpoints are safety, quality of life, use of wig or cap, and success rates after the completion of all cycles of chemotherapy distinguished by anthracycline(AC) and taxane.

The cooling device is the Paxman scalp cooling system. Scalp cooling was performed from 30 mins before initiation until 90 mins (25 min for taxane) after chemotherapy. Pictures of the scalp were taken at the time of the initiation of each course.

Statistical methods

Successful treatment was defined as the presence of less than 50% of hair-loss area. The sample size was calculated using the Simon method, with a type I error of 10% (two-sided) and a study power of 80%.The expected success rate is 30%, with a threshold success rate of 10%, and the required number of patients was estimated to be 19.

Present and target accrual

Patient accrual was started in April 2018 and present accrual is 3. We plan to enroll a total of 20 patients in the trial.

Citation Format: Kodera A, Ogura K, Hattori A, Yukawa H, Sakaguchi S, Matsuoka A, Tanaka N, Kamimura M, Jibiki N, Naritaka Y, Hirano A. Efficacy and safety of scalp cooling device for prevention of alopecia in patients with 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 OT1-05-03.
Abstract OT1-09-01: Phase II trial assessing accuracy of tumor bed biopsies in predicting pathologic response in patients with clinical/radiological complete response after neoadjuvant chemotherapy in order to explore the feasibility of breast-conserving surgery without surgery: NRG Oncology BR005
Authors: Basik M , Costantino JP , De Los Santos JF , Umphrey HR , Julian TB , Mamounas EP , White JR , Lucas PC , Wagner JL , Tjoe JA , Thompson AM , Wolmark N
Published: May 2019

The increased use of neoadjuvant chemotherapy (NCT) has enabled higher rates of breast-conserving surgery (BCS) as well as provided prognostic information for women with breast cancer. High pathological complete response (pCR) rates question the requirement for surgery, with its attendant morbidity. In order to avoid surgery, the ability to predict pCR prior to it must be very high. Trimodality imaging alone is inadequate to predict pCR prior to surgery. We hypothesize that performing core-needle biopsy (bx) of the tumor bed in addition to trimodality imaging in patients (pts) having had a clinical complete response (cCR) will increase the ability to predict pCR. Utilizing predetermined imaging response criteria of complete or near-complete response coupled with a stereotactic core-needle bx of the tumor bed, BR005 aims to determine the predictive value of imaging followed by tumor bed bx for pCR and demonstrate its reproducibility across a multi-institutional setting.

Methods: 175 pts with operable focal or multifocal (T1-T3), stage II/IIIA invasive ductal carcinoma (all receptor subtypes) will be entered. Pts must have completed a minimum of 8 wks of standard NCT and achieved a complete or near-complete radiologic tumor response on breast imaging with mammogram, ultrasound, and MRI, and undergo BCS. Following cCR and prior to surgery, pts will undergo a stereotactic-vacuum-assisted breast bx with clip placement. The primary endpoint is the proportion of pts with post-NCT neg image-directed bx who have a pCR. Residual cancer burden scores and core bx pathology will be collected along with trimodality imaging data. Evaluation after 135 pts will allow for the possibility of early termination of the study. Results will provide the first step toward a paradigm change in the treatment of breast cancer, enabling a study to assess the criteria for successful avoidance of surgery in pts with high response rates to NCT.

Accrual as of 6-15-18: 39 (22.3%).

Support: U10CA180868, -180822, UG1CA189867.

Citation Format: Basik M, Costantino JP, De Los Santos JF, Umphrey HR, Julian TB, Mamounas EP, White JR, Lucas PC, Wagner JL, Tjoe JA, Thompson AM, Wolmark N. Phase II trial assessing accuracy of tumor bed biopsies in predicting pathologic response in patients with clinical/radiological complete response after neoadjuvant chemotherapy in order to explore the feasibility of breast-conserving surgery without surgery: NRG Oncology BR005 [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 OT1-09-01.
Abstract OT1-12-02: Biomarker study of patients with HER2-negative metastatic breast cancer receiving combination therapy with nivolumab, bevacizumab and paclitaxel as first-line treatment (WJOG9917BTR)
Authors: Ozaki Y , Kitano S , Matsumoto K , Takahashi M , Mukohara T , Futamura M , Masuda N , Tsurutani J , Yoshimura K , Minami H , Takano T
Published: May 2019

Background: In recent years, anti-PD-1 antibody, an immune checkpoint inhibitor, has been developed for the treatment of various types of cancer, including breast cancer. Synergistic effects of nivolumab, paclitaxel and bevacizumab are expected, based on various preclinical data, when these drugs are administered in combination. A biomarker study is ongoing to evaluate the immune status of patients participating in the NEWBEAT trial, which is a phase II trial of nivolumab + paclitaxel + bevacizumab therapy as first-line treatment for patients with metastatic or recurrent HER2-negative breast cancer. Methods: HER2-negative breast cancer patients from the WJOG9917B (NEWBEAT) trial are enrolled in this biomarker study. To explore new biomarkers for combined treatment of breast cancer with immune-checkpoint inhibitors and anti-vascular endothelial growth factor antibodies, we propose to conduct multicolor immunohistochemistry (IHC) assays for immunomonitoring of the intra-tumor environment, such as the expressions of PD-L1, CD4 and CD8. Blood samples are collected before the start of treatment and at four time-points during the treatment, to determine, using a multicolor flow cytometry panel, the numbers of circulating immunosuppressive cells, such as regulatory T cells, myeloid-derived suppressor cells and tumor-associated macrophages (M2). In the NEWBEAT trial, patients receive nivolumab 240 mg/body on days 1 and 15, paclitaxel 90 mg/m2 on days 1, 8 and 15, and bevacizumab 10 mg/kg on days 1 and 15 every 4 weeks until disease progression. The primary endpoint is the objective response rate, and the key secondary endpoints include progression-free survival, overall survival, and toxicity of the protocol treatment. A total of 51 patients will be enrolled and the enrollment period will be one year. This trial opened to accrual in February 2018. Clinical trial registry number: UMIN000029590

Citation Format: Ozaki Y, Kitano S, Matsumoto K, Takahashi M, Mukohara T, Futamura M, Masuda N, Tsurutani J, Yoshimura K, Minami H, Takano T. Biomarker study of patients with HER2-negative metastatic breast cancer receiving combination therapy with nivolumab, bevacizumab and paclitaxel as first-line treatment (WJOG9917BTR) [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 OT1-12-02.
Abstract OT1-13-02: Molecular testing for minority patients with or at high risk for cancer
Authors: Singh R , Bayan MA , Kadari S , Nganteh MN , Jacksonm M , Woodson LM , Shamsuddin AS , Lemus BY , Pratap S , Murray JJ , Adunyah SE , Lammers PE
Published: May 2019

PURPOSE: Meharry Medical College is a participant in eMERGE (Electronic Medical Records and Genomics); a multicenter network sponsored by NHGRI/NIMHD with the primary goal to develop, disseminate, and apply approaches to research that combine biorepositories with electronic medical records (EMR) for genomic discovery and medicine implementation research. The consortium also focuses on ethical issues involving privacy, confidentiality, and interaction with the broader community. Individual institutions created protocols around research questions individualized to their populations.

METHODS: We enrolled 500 African Americans with or at high-risk for the four most common cancers (prostate, colorectal, breast, lung) to examine possible genetic and proteomic differences to account for health disparities in this population. We will perform DNA, RNA, and proteomics analyses pertinent to these cancers and obtain corresponding clinical history from the EMR with planned long-term follow up.

RESULTS: 500 subjects (211 female) were enrolled over 11 months from Nashville General Hospital including the following cancer/at-risk participants (Breast 59/37; Colorectal 17/128; prostate 31/136; lung 16/76). Most individuals stated that they participated for potential benefit to themselves, family members, or humankind and only 11 percent of potential participants declined. Little concern has been voiced for providing samples for genetic analysis. A genetic counselor will meet with the participants that are found to have pathogenic or likely pathogenic mutations while study investigators will share results with those that are not found to have mutations. Participants will be queried regarding understanding of the genetic testing results and followed for one year to evaluate if they underwent recommended testing and to follow for cancer outcomes.

CONCLUSION: The inclusion of diverse groups in genomic research is critical to identify possible reasons for health disparities and to study the understanding of genetic testing and ethical issues surrounding this topic. In this study, African-Americans are participating willingly in clinical research to examine possible genetic and/or social bases for cancer disparities.

ACKNOWLEDGEMENT: NIMHD (U54MD007593) to the Meharry Translational Research Center (MeTRC); National Human Genome Research Institute (NHGRI); National Institute of Allergy and Infectious Disease (NIAID).

Citation Format: Singh R, Bayan MA, Kadari S, Nganteh MN, Jacksonm M, Woodson LM, Shamsuddin AS, Lemus BY, Pratap S, Murray JJ, Adunyah SE, Lammers PE. Molecular testing for minority patients with or at high risk for 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 OT1-13-02.
Abstract OT2-02-01: A confirmation study of omitting axillary dissection in patients with breast cancer and positive sentinel nodes
Authors: Jibiki N , Hirano A , Ochi T , Sakamoto A , Horiuchi K , Noguchi E , Omi Y , Ogura K , Inoue H , Kamio T , Naritaka Y , Fujibayashi M , Hiroshima K , Nagashima Y , Sakai S , Karasawa K , Okamoto T
Published: May 2019

Background

The omission of axillary dissection for positive sentinel-node breast cancer is considered the standard treatment for patients who undergo breast conserving surgery and radiation therapy, according to the results of ACOSOG-Z0011 and AMAROS trials. On the other hand, some surgeons still think that the surgical stress of axillary dissection is minimal, and dissection is permitted. Furthermore, Z0011 contains several problems, such as insufficient number of entry cases and lack of radiation field unity. Thus, we planned a prospective trial to confirm the safety of omitting axillary dissection in patients with breast cancer and positive sentinel nodes.

Trial design

This is a single arm, confirmation study of three medical centers. Prior to surgery, informed consent is obtained, and patients are registered primarily. After surgery, patients with 1 to 2 positive sentinel nodes, for whom axillary dissection was omitted, are finally included in this trial at final registration.

Eligibility criteria

Patients with histologically-diagnosed breast cancer, Tis–2, N0 based on a core needle biopsy, will be included in this trial. Eligible patients must be between 20 and 80 years of age, with a performance status of 0–2 and adequate organ function. They must not have undergone any prior operation, radiation therapy, chemotherapy, endocrine therapy, or immunotherapy.

Specific aims

The primary endpoint is 5-year (y) axillary recurrence rate. Secondary endpoints are 5-y overall survival, 5-y recurrence-free survival, 5-y local recurrence-free survival, the rate of upper-limb lymphedema, quality of life, and comparison of axillary recurrence rates between patients with two or more dissected nodes and those with only one positive node.

Statistical methods

The expected rate of axillary recurrence is 2.0%, and non-inferiority is defined as an axillary recurrence lesser than or equal to 5% in the axillary radiotherapy group. The sample size was calculated with a study power of 80% and type I error of 10% (two-sided). The required number of patients is estimated to be 189.

Present and target accrual

Patient accrual from the three medical centers was initiated in July 2016. We plan to enroll a total of 189 patients at final registration in this trial.

Citation Format: Jibiki N, Hirano A, Ochi T, Sakamoto A, Horiuchi K, Noguchi E, Omi Y, Ogura K, Inoue H, Kamio T, Naritaka Y, Fujibayashi M, Hiroshima K, Nagashima Y, Sakai S, Karasawa K, Okamoto T. A confirmation study of omitting axillary dissection in patients with breast cancer and positive sentinel nodes [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 OT2-02-01.
Abstract OT2-06-01: Highly innovative personalized RNA-immunotherapy for patients with triple negative breast cancer
Authors: Schmidt M , Bolte S , Frenzel K , Heesen L , Derhovanessian E , Bukur V , Diken M , Gruetzner J , Kreiter S , Klein A , Kuhn A , Langer D , Loewer M , Lindman H , Schneeweiss A , Tuereci O , Sahin U
Published: May 2019

Background: The treatment of triple negative breast cancer (TNBC) is hampered by the lack of established therapeutic targets such as hormone receptors or HER-2. Chemotherapy and radiotherapy is the standard of care, yet survival rates in TNBC remain poor. Approaches tailored to the patient's individual tumor signature may lead to improved therapeutic outcome. We have set up a clinical workflow covering drug development (from target discovery to manufacturing) and drug release providing a custom-made investigational medicinal product (IMP) for each individual patient.

Trial Design: A phase I/II trial assesses the feasibility, safety and biological efficacy of this personalized immunotherapy in three clinical sites in Germany and Sweden. TNBC patients (pT1cN0M0 – TxNxM0) after completion of initial standard of care therapy will be allocated to one of two study arms. Patients in ARM1 receive 8 vaccination cycles with a personalized combination of shared tumor-associated antigens, selected based on each patient tumor's antigen-expression profile out of a WAREHOUSE of pre-manufactured mRNA vaccine. Patients in ARM2 receive the personalized mRNA WAREHOUSE vaccine followed by 8 vaccination cycles of an on-demand manufactured mRNA MUTANOME vaccine encoding up to twenty unique neo-epitopes of the individual patient identified by next generation sequencing. The mRNAs are administered intravenously as a nanoparticulate lipoplex formulation, which protects RNA from degradation, activates innate immunity, transfects APCs and consequently induces highly potent antigen-specific T-cell responses. The treatment of 12 patients in ARM1 is completed and enrolment of patients for ARM2 has started. Preliminary data show that the RNA-WAREHOUSE approach is feasible and can be applied safely. Biomarker analysis is ongoing. This approach is promising as it addresses the heterogeneity of TNBC.

The TNBC-MERIT trial was initially funded by the EU Commission's FP7 and led by BioNTech AG.

Citation Format: Schmidt M, Bolte S, Frenzel K, Heesen L, Derhovanessian E, Bukur V, Diken M, Gruetzner J, Kreiter S, Klein A, Kuhn A, Langer D, Loewer M, Lindman H, Schneeweiss A, Tuereci O, Sahin U. Highly innovative personalized RNA-immunotherapy for patients with triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-06-01.
Abstract OT3-03-03: PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients
Authors: Abraham J , Vallier A-L , Qian W , Machin A , Grybowicz L , Thomas S , Weiss M , Harvey C , McAdam K , Hughes-Davies L , Roberts A , Roylance R , Copson E , Pinilla K , Armstrong A , Provenzano E , Tischkowitz M , McMurty E , Earl H
Published: May 2019

Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC sub-group share some phenotypic and molecular similarities with germline BRCA (gBRCA) tumours. In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (Olaparib) to work more effectively. Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)).

Methods: Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. Stage 1 and 2: Randomisation (1:1:1) to either control (3 weekly carboplatin AUC5/weekly paclitaxel 80mg/m2 for 4 cycles) or one of two research arms with the same chemotherapy regimen but with two different schedules of olaparib 150mg BD for 12 days. Stage 3: Patients are randomised (1:1) to either control arm or to the research arm selected in stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection using pCR rate and completion rate of olaparib using a “pick-the-winner” design. Stage 3: pCR rate. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A total of 527 patients will be included to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by adding olaparib to platinum based chemotherapy.

Trial Progress: PARTNER has been recruiting in UK since 27th May 2016. IDSMC recommended to continue the trial without change after reviewing the Stage 1 safety data. The recruitment of stage 2 was completed in April 2018 and results to be reviewed by the IDSMC in early 2019. The trial is open and enrolling patients to national and international sites.

Citation Format: Abraham J, Vallier A-L, Qian W, Machin A, Grybowicz L, Thomas S, Weiss M, Harvey C, McAdam K, Hughes-Davies L, Roberts A, Roylance R, Copson E, Pinilla K, Armstrong A, Provenzano E, Tischkowitz M, McMurty E, Earl H. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer 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 OT3-03-03.
Abstract P1-02-06: Breast cancer screening in the Republic of Belarus: Advantages and learning perspective
Authors: Trusova O , Osharin V , Smelov V , Wilkinson L , Given-Wilson R
Published: May 2019

Background:

Breast cancer (BC) is the most common cancer among women in the Republic of Belarus. To reduce BC-related mortality, the implementation of organized pilot BC screening programmes using digital mammography has been supported by the European Union as part of the BELMED project. During recent years Belarus has developed its own digital mammographs and software that allows storing and processing images in the DICOM format. To assure digital mammographic performance in the local context, the first external clinical image quality assessment (QA) of Belarus mammograms was performed by a leading UK radiologist.

Methods:

The reviewed mammograms from 88 (out of 2,267) Belarus women (mean age: 59.5 years; SD:5.7) attending the a breast screening pilot in Minsk were examined as 81 with positive and 7 with negative findings, according to Belarus readers. This included all 10 histologically confirmed BCs. Within the framework of BELMED project, a total of 400 mammographic images were selected for evaluation by a leading expert radiologist from the UK Public Health England Breast Screening Programme. Evaluated mammographic images were classified according to the Belarus (non-BIRADS) and BIRADS (the UK radiologist) categories, associtated with a follow-up plan. Gradings were compared across categories (the Cohen's Kappa) and according to the proportion of cases referred for further tests (the Wilcoxon signed rank test).

Results:

The reviewer concluded that approximately 50% of the positive mammograms didn't require futher assessment in screening according to the UK radiologist. All histologically confirmed BCs were not among those downgraded. Substantial agreement was found in the gradings for BC (Kappa: 0.66, p<0.001). The study has resulted in adopting the BIRADS classification in the country and launching additional training of radiologists (e.d. in biopsy) and radiographers (in positioning).

Conclusions:

To minimize additional tests on women, comprehensive QA (audit and regular check of mammographic technique, the opinion of physicists, etc.) is essential. Applying the implementation research may result in further improvement of the national BC programme. Improved practice can be promoted by continous image review and training for individual staff (i.e., through BELMED, in collaboration with UK training centres) to further improve the skills of Belarus specialists and increase the quality of BC screening programme in Belarus.

Citation Format: Trusova O, Osharin V, Smelov V, Wilkinson L, Given-Wilson R. Breast cancer screening in the Republic of Belarus: Advantages and learning perspective [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-02-06.
Abstract P1-02-08: Withdrawn
Authors: Ellsworth Beaumont C , Nwankwo E
Published: May 2019

This abstract was withdrawn by the authors.

Citation Format: Ellsworth Beaumont C, Nwankwo E. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-02-08.
Abstract P1-04-01: Estrogen receptor β agonists inhibits syngeneic mammary tumor growth through cell-cycle arrest by modulating cell-cycle regulators
Authors: Ramasamy K , Samayoa C , Krishnegowda NK , Thurlapati A , Vadlamudi RK , Tekmal RR
Published: May 2019

Breast Cancer is the main cause of cancer-associated mortality in women worldwide. The estrogen receptors (ER's) play an important role in normal mammary gland development, as well as in breast cancer. Estrogen Receptor α is expressed in 70% of breast cancers, where it contributes to increased cell proliferation and decreased cell death. Endocrine therapies such as anti-estrogens and aromatase inhibitors target ERα signaling and improve outcomes of these patients. Syngeneic, immunocompetent mouse models are essential for elucidating the mechanisms and for evaluating novel strategies for the treatment of breast cancer. In contrast to the tumor-inducing role of ERα, ERβ has been shown to have tumor suppressive activities in various cancer, including the breast cancer. Compounds that selectively activate ERβ hold promise because they could potentially avoid the unwanted effects of ERα activation, while exploiting the tumor-suppressive function of ERβ. In the present study, we assessed the antitumor effects of ERβ agonists using three different syngeneic mouse models; D2A1 (BALB/c) and MM51 (FVB) syngeneic models and ex-vivo culture of highly metastatic cell line E0771 (C57/B6). Effect on in vitro cancer cell growth was evaluated by cell proliferation and clonogenic assays. Cell cycle distribution was analysed by flow cytometry. Our results demonstrate that ERβ agonists LY500307 and S-Equol not only inhibited the growth of all three mouse mammary tumor cell lines, but also reduced the colony formation ability. ERβ agonists also induced the cell-cycle arrest in time and dose-dependent manner. In mechanistic studies, ERβ agonists LY500307 and S-Equol, modulated the protein levels of cyclin-dependent kinases (CDKs) (4, 6, and 2), cyclins (D1 and E), in a differential manner in these three cell lines. Our in vivo studies of D2A1 and MM51 cells demonstrates that ERβ agonist LY500307 inhibited the tumor growth and the effect was more pronounce in combination with aromatase inhibitor letrozole. Ex-vivo model of E0771 cells showed that LY500307 has potential to dramatically reduce the proliferation of mouse mammary tumor growth.Together, these results identify potential molecular targets and anticancer effects of ERβ agonists in mouse mammary tumors.

Citation Format: Ramasamy K, Samayoa C, Krishnegowda NK, Thurlapati A, Vadlamudi RK, Tekmal RR. Estrogen receptor β agonists inhibits syngeneic mammary tumor growth through cell-cycle arrest by modulating cell-cycle regulators [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-04-01.
Abstract P1-05-05: eEF1A2 facilitates PTEN-GSK3β mediated Aurora-A protein degradation during S-G2 phase inactivated in PTEN-deficient breast cancer
Authors: Treekitkarnmongkol W , Solis LM , Kai K , Thompson AM , Tian W , Wistuba II , Sasai K , Jltsumori Y , Sahin AA , Hawke DH , Lee JM , Qin L , Bawa-Khalfe T , Rad R , Wong KK , Abbott CM , Katayama H , Sen S
Published: May 2019

The AURKA gene, encoding Aurora kinase-A (Aurora-A), is frequently amplified and overexpressed across multiple cancer types correlating with poor prognosis. Although the AURKA gene is frequently amplified in human cancers, underlying mechanism(s) for Aurora-A protein stability through different phases of cell cycle are not well elucidated. Inhibiting the kinase activity and promoting protein degradation are two well-validated conceptual strategies for targeting protein kinases in cancers. Here, we demonstrate that Eukaryotic Elongation Factor 1 Alpha 2 (eEF1A2) facilitates PTEN-GSK3β mediated Aurora-A protein degradation through the SCF complex (SKP1-Cul1-FBXW7) during the S/G2 phase of proliferating cells. In contrast, this mechanism is inactivated in cancer cells accompanying PTEN-GSK3β pathway deficiency. Mechanistically, eEF1A2 interacts with Aurora-A, GSK3β, FBXW7 and Cul1-E3 ligase, as the SCF complex, to facilitate Aurora-A polyubiquitination for 26S proteasomal degradation. eEF1A2 promotes PTEN phosphorylation at T366 and stability, inactivates AKT and activates GSK3β which in turn phosphorylates Aurora-A at S283, S284 and S342. The phosphorylation of Aurora-A at S342 is detected during S/G2 phase of cell mitosis in parallel with eEF1A2-SCF complex formation with active form of GSK3β and neddylated Cul1. Conversely, genetic ablation of EEF1A2 and PTEN, activation of AKT, inhibition of GSK3β, expression of Aurora-A phosphodeficient-mutant attenuates the Aurora-A protein degradation which is corroborated in Aurora-A overexpressing mouse mammary carcinomas and human breast carcinomas. This study identifies a novel mechanism of Aurora-A protein degradation mediated eEF1A2-PTEN-GSK3β pathway and provides a framework for the discovery of Aurora-A therapeutic targets in breast cancer that harbors deficiency of PTEN tumor suppressor pathway.

Citation Format: Treekitkarnmongkol W, Solis LM, Kai K, Thompson AM, Tian W, Wistuba II, Sasai K, Jltsumori Y, Sahin AA, Hawke DH, Lee JM, Qin L, Bawa-Khalfe T, Rad R, Wong KK, Abbott CM, Katayama H, Sen S. eEF1A2 facilitates PTEN-GSK3β mediated Aurora-A protein degradation during S-G2 phase inactivated in PTEN-deficient 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 P1-05-05.
Abstract P1-06-03: A selective Cdk12/13 non-covalent inhibitor with potent anti-breast cancer activity
Authors: Quereda V , Bayle S , Francesca V , Andrii M , William R , Derek D
Published: May 2019

Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) are Ser/Thr protein kinase members of the CDK family. CDKs are regulated by cyclins and members of the family are key regulators of the cell cycle. Other members of this family—CDK7, CDK8, CDK9, CDK12 and CDK13—have been described as transcription-regulating kinases. CDK12 and CDK13 phosphorylate the C-terminal domain (CTD) of rpb1 the largest subunit of RNA polymerase II and interact with RNA processing factors, playing pivotal roles controlling transcription initiation and elongation, as well as posttranscriptional RNA processing. Specifically, CDK12 acts as the limiting factor for the transcription of a small subset of genes that are involved in the DNA damage response pathway and CDK13 affects expression of genes involved in growth signaling pathways. Importantly, like their cell cycle family members CDK12 and CDK13 have also been shown to be promising therapeutic targets for several cancer types. We have generated a novel, selective, and orally bioavailable, small molecule inhibitor of CDK12 and CDK13. Our lead molecule downregulates key DNA damage repair proteins including ATM, ATR, Brca1 and Rad51 leading to induction of apoptotic cell death in all triple negative breast cancer (TNBC) cell lines tested. We have confirmed the selectivity of our compound by kinase profiling and by comparing the gene expression profile by RNA-seq of cells treated with compound or infected with CRISPR sgRNA targeting Cdk12 and/or Cdk13. Importantly, our compound acts in synergy with the chemotherapeutic agents Cisplatin, Irinotecan and Olaparib. Finally, in preclinical efficacy studies, our lead compound blocked tumor progression in two different PDX models of TNBC and demonstrated tumor regression and enhanced efficacy over single treatment when dosed in combination with selected chemotherapeutic agents.

Citation Format: Quereda V, Bayle S, Francesca V, Andrii M, William R, Derek D. A selective Cdk12/13 non-covalent inhibitor with potent anti-breast cancer activity [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-06-03.