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SL-02Proteogenomics of Breast CancerLester and Sue Smith Breast Cancer, Baylor College of MedicineMatthew J. Ellis

Cancer proteogenomics combines information from genomics, transcriptomics and mass spectrometry-based proteomics to gain insights into cancer biology and treatment responsiveness. To promote clinical applicability the NCI Clinical Proteomic Tumor Analysis Consortium has funded a Proteogenomic Translational Research Center focused on early stage Breast Cancer. The driving analytical principle for this effort at the Broad Institute in Boston and Baylor College of Medicine in Houston is a microscaled proteogenomics approach whereby a single tumor-rich OCT embedded 14G needle core biopsy is sufficient for deep-scale nucleic acid and peptide sequencing. As proof-of-concept, we have analyzed core biopsies obtained before and within 48 to 72 hrs of the first dose of neoadjuvant trastuzumab-based chemotherapy for HER2+ breast cancer. By comparing samples associated with complete pathological response versus residual disease, multiple a priori mechanisms of treatment resistance can be diagnosed. Ongoing analyses of triple negative breast cancer and luminal breast cancers undergoing neoadjuvant therapy will eventually allow us to dissect the signaling networks that drive resistance across all subtypes of breast cancer.

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IL-01Psychosocial and end-of-life EOL aspects of palliative care PC into the daily practice1 Integrated Cancer Rehabilitation Cancer Fatigue Clinic, Klinik Gais AG 2Clinic Medical Oncology and Hematology, Dept. Internal Medicine, Cantonal Hospital St.GallenFlorian Strasser1,2

Current evidence demonstrates that specialized PC integrated early in modern oncology care pathways is associated with improved QoL and symptom control,caregivers burden and variably with survival or health resource use. This demands oncology professionals oncologists, oncology nurses to screen for needs for and deliver PC-Interventions PCIs in daily cancer care, consistent with the competences delineated in the global ESMO/ASCO curriculum for medical oncologists.

PCIs encompass illness and prognosis understanding, multi-modal symptom management, structured decision making processes, coping with threatened existence, suffering, and changed hope, EOL preparation, support network building, support of family members and addressing spiritual issues. High intensity, complex, or interferring PCIs demand specialist PC teams.

Psychosocial PCIs encompass:Addressing illness understanding, discuss prognostic awareness, dealing with both limited time left, existential threat and longterm survival likelihoods in modern cancer care, breaking bad news, reframing hope, structured decision making process for or against another anti-cancer treatment in palliative intention, dealing with children or parents as cancer patient, healthy and unhealthy denial, conscious collusion, opening conspiracy of silence and addressing trust in the patient-physician-relationship. EOL PCIs encompass:include legacy work, premortal preparation for post mortal roles, conscious bucket lists, premortal preparation for post mortal grief, value based, dynamic advanced care planning, preparing for the dying phase, spiritual/transcendental and religious isses, and funeral preparation.

Advanced communication skills, a transprofessional team approach, self-care strategies and institutional support strenghten medical oncologists holistic approach.Exchanging experiences and concepts of cultural and religious circumstances distinguished from conservatisms and traditionalisms also merits attention.

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IL-02Current treatment landscape for the management of ER+ HER2- Advanced Breast CancerUniversity of Nottingham, Graduate Entry Medical School, University Hospitals of Derby & Burton NHS Foundation TrustJohn Robertson

In 1980s the sequence of tamoxifen, Megace and aminoglutethimide was based on side-effects. Today the sequence of fulvestrant Selective Estrogen Receptor Downregulator, SERD, a 3rd generation aromatase inhibitorAI and tamoxifen is based of improved efficacy: only fulvestrant 500mg has consistently shown an improvement in overall survivalOS. Further lines of ET are reserved for tumours responsive to previous ETs.

More recently therapies which inhibit other cellular pathways eg EGFR, PI3KCA, AKT, mTOR, IFGR, FGFR, modulate the cell cycle eg CDK 4/6 inhibitors, inhibit histone deacetylase HDACi, target immune checkpoints have been researched in combination with ET. Only mTOR inhibition, and CDK 4/6 inhibitors have thus far found their way into routine use yet neither of these have significantly improved OS in Phase 3 trials. HDACi and immunotherapy remains a research question.

Other factors are site of disease and with visceral metastases VMs also extent of disease. A recent meta-analysis of 5,000 patients in Phase 3 ABC trials reported that non-VMs did significantly better than VMs. Furthermore non-liver VMs did better than liver VMs. Patients with non-VMs who receive fulvestrant 500mg monotherapy appear by indirectly comparison to have similar clinical benefit and progression free survival as those who receive an AI + CDK 4/6 inhibitor. In addition, in 1st-line, fulvestrant showed a significant improvement in OS compared to an AI whereas an AI+CDK4/6 inhibitor did not improve OS compared to an AI. Similarly in 2nd line ET a CDK 4/6 inhibitor did not improve OS.

There is currently no universal standard for 1st-line therapy nor a standard sequence of therapies. Management of these patients should consider the following evidence of sensitivity to prior ET, ETs available, sites of disease VM or non-VM, especially liver mets, extent of liver mets, patient s co-morbidities and importantly both cost-effectiveness and a patient s choice of treatment.

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IL-03Why are advances so slow in advanced breast cancer? Challenges and InequalitiesBreast unit, Champalimaud Clinical Centre, PORTUGALFatima Cardoso

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inScience Communications30 medical writing inScience Communications medical writer OPEN To Overcome failure to Publish nEgative fiNdings; www.open-project.euScherer full-length 1

Reference: 1 Scherer RW et al., Authors report lack of time as main reason for unpublished research presented at biomedical conferences: a systematic review. J Clin Epidemiol. 2015 Jul;687:803-10.

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Breast Cancer199426Springer Japan219974201462010Impact Factor20181.772201850019.719511972563359.7%14.6%5.8%216Associate EditorReviewerReview article, Special articleBreast CancerBreast Cancer

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MTE-01Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer CenterNaoto T. Ueno

1989 M.D., Wakayama Medical College Wakayama, Japan1990 Clinical Internship United States Naval Hospital Yokosuka, Kanagawa, Japan1991 Internal Medicine Montefiore University Hospital University of Pittsburgh - Pittsburgh, PA1993 Internal Medicine University of Pittsburgh Medical Center Pittsburgh, PA1993 Present Professor, The University of Texas MD Anderson Cancer Center Houston, TX 1996 Clinical Fellowship The University of MD Anderson Cancer Center - Houston, TX1999 Ph.D. The University of Texas Graduate School of Biomedical Sciences Houston, TX

Specialty and Research Field of Interest

Medical Oncology and Translational Breast Cancer ResearchTriple Negative Breast Cancer, Inflammatory Breast Cancer, Drug Development

Recent Selected Publications

1. Nik-Zainal S, et al, Krishnamurthy S, et al, Ueno NT, et al, Thompson AM, et al, Stratton MR. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 2016. PMID: 27135926.

2. Lim B, Woodward WA, Wang X, Reuben JM, Ueno NT. Inflammatory breast cancer biology: the tumor microenvironment is key. Nature reviews. Cancer. 2018; 18(8):485-499. PMID: 29703913

3. Bartholomeusz C, et al, Ueno NT. PEA-15 inhibits tumorigenesis in an MDA-MB-468 triple-negative breast cancer xenograft model through increased cytoplasmic localization of activated extracellular signal-regulated kinase. Clin Cancer Res. 2010;16:1802-11. PMID: 20215547.

4. Bartholomeusz C, Xie X, Pitner MK, Kondo K, Dadbin A, Lee J, Saso H, Smith PD, Dalby KN, Ueno NT. MEK Inhibitor Selumetinib Prevents Lung Metastasis in a Triple-Negative Breast Cancer Xenograft Model. Mol Cancer Ther. 2015;14:2773-81. PMID: 26384399; PMCID: PMC4674314.

5. Kai K, Iwamoto T, Kobayashi T, Arima Y, Takamoto Y, Ohnishi N, Bartholomeusz C, Horii R, Akiyama F, Hortobagyi GN, Pusztai L, Saya H, Ueno NT. Ink4a/Arf(-/-) and HRAS(G12V) transform mouse mammary cells into triple-negative breast cancer containing tumorigenic CD49f(-) quiescent cells. Oncogene. 2014;33:440-8. PMID: 23376849; PMCID: PMC3957346.

6. Wang X, Reyes ME, Zhang D, Funakoshi Y, Trape AP, Gong Y, Kogawa T, Eckhardt BL, Masuda H, Pirman DA, Jr., Yang P, Reuben JM, Woodward WA, Bartholomeusz C, Hortobagyi GN, Tripathy D, Ueno NT. EGFR signaling promotes inflammation and cancer stem-like activity in inflammatory breast cancer. Oncotarget. 2017;8:67904-17. PMID: 28978083; PMCID: PMC5620223.

7. Xie X, Kaoud TS, Edupuganti R, Zhang T, Kogawa T, Zhao Y, Chauhan GB, Giannoukos DN, Qi Y, Tripathy D, Wang J, Gray NS, Dalby KN, Bartholomeusz C, Ueno NT. c-Jun N-terminal kinase promotes stem cell phenotype in triple-negative breast cancer through upregulation of Notch1 via activation of c-Jun. Oncogene. 2017;36:2599608. PMID: 27941886

8. Umehara H, Maekawa Y, Koizumi F, Shimizu M, Ota T, Fouad TM, Willey J, Kaito H, Shiraishi N, Nakashima D, Akinaga S, Ueno NT. Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole. Therapeutic advances in medical oncology. 2018; 10:1758835918786858. PMID: 30083253, PMCID: PMC6066809

9. Matsuda N WX, Lim B, Krishnamurthy S, Alvarez RH, Willey JS, Parker CA, Song J, Shen Y, Hu J, Wu W, Li N, Babiera GC, Murray JL, Arun BK, Brewster AM, Reuben JM, Stauder MC, Barnett CM, Woodward WA, Le-Petross C, Lucci A, DeSnyder SM, Tripathy D, Valero V, and Ueno NT. Safety and Efficacy of Panitumumab Plus Neoadjuvant Chemotherapy in Patients With Primary HER2-Negative Inflammatory Breast Cancer. JAMA Oncology. 2018; 4:1207-1213. PMID: 29879283.

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MTE-03Johns Hopkins School of MedicineVered Stearns

Co-Director, Breast and Ovarian Cancer ProgramProfessor of OncologyBreast Cancer Research Chair in OncologyMedical-Director, Under Armour Breast Health Innovation CenterSidney Kimmel Comprehensive Cancer CenterJohns Hopkins School of Medicine

Dr. Vered Stearns completed a B.S. equivalent at the Tel Aviv University, Sackler Faculty of Medicine in 1989. After relocating to the United States, Dr. Stearns transferred to and graduated from the University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School in 1992. She completed a residency in Internal Medicine and a fellowship in Medical Oncology at the Georgetown University where she developed an interest in translational breast cancer research and spent two additional years as a research fellow. Dr. Stearns was a faculty member at the Lombardi Comprehensive Cancer Center and the Georgetown University, and at the University of Michigan Comprehensive Cancer Center in Ann Arbor, Michigan before joining the faculty at the Breast Cancer Program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in 2002. She has since been appointed as co-Director of the Breast Cancer Program in 2010, and to full Professor in 2013. In 2014 she was appointed at the co-Director of the Breast and Ovarian Cancer Program at the Kimmel Cancer Center at Johns Hopkins. In 2018 she became the inaugural Medical Director of the Under Armour Breast Health Innovation Center.

Dr. Stearns s long-term research goal is to improve current therapies by individualizing strategies for the treatment and prevention of breast cancer. Her main research includes utilization of biomarkers to predict response to standard regimens used to treat and prevent breast cancer and to introduce new interventions. Dr. Stearns and colleagues from the Consortium On Breast Cancer Pharamcogenomics (COBRA) Group were the first to evaluate the role of genetic variants in candidate genes such as CYP2D6 in tamoxifen metabolism, safety, and efficacy. The work has been extended to evaluate the role of genetic variants in aromatase inhibitor associated outcomes.

Dr. Stearns has received numerous grants and awards to fund her innovative research. She was a recipient of early career awards including a Clinical Research Training Grant from the American Cancer Society, and was one of the first five recipients of the prestigious Damon Runyon Clinical Investigator Award. Subsequently she was the inaugural recipient of the American Society of Clinical Oncology s Advanced Clinical Research Award. She is an Editorial Board Member Clinical Cancer Research, Breast Cancer Research and Treatment, and ONCOLOGY.

Dr. Stearns s work has been presented in key national meetings such as the American Society of Clinical Oncology, American Association for Cancer Research, and the San Antonio Breast Cancer Symposium. Her work has been published in high-impact peer-reviewed journals such as the Journal of the National Cancer Institute, Journal of Clinical Oncology, JAMA, and Clinical Cancer Research. Her work has been cited extensively and has already had a positive impact on the lives of many women. Indeed, in 2017 she was selected by Forbes as one of 27 top breast cancer oncologists in the US.

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MTE-041Surgery, Harvard Medical School2Breast Program, Massachusetts General Hospital3Division of Surgical Oncology, Massachusetts General HospitalBarbara L. Smith1,2,3

Barbara L. Smith, MD, PhD is the Director of the Breast Program at Massachusetts General Hospital and a member of the Division of Surgical Oncology at MGH. She is a Professor of Surgery at Harvard Medical School. Dr. Smith received her undergraduate training at Massachusetts Institute of Technology, an MD from Harvard Medical School s Harvard/MIT Division of Health Sciences and Technology and a PhD in Microbiology and Molecular Genetics from Harvard University Graduate School of Arts and Sciences.

Dr. Smith s research activities have focused on reducing the extent of surgery and radiation required to treat breast cancer, improved approaches for lumpectomy margin assessment, and 3-dimensional breast anatomy as it relates to breast surgery and pathologic analysis of specimens, including nipple sparing mastectomies. She has developed a novel technique for an oncologically safe and cosmetically superior nipple sparing mastectomy. She is the PI of 2 NIH-funded multicenter trials of the Lumicell Imaging System in breast cancer lumpectomy margin assessment.

Dr. Smith is Chair of the Society of Surgical Oncology Breast Program Directors Committee and Co-Director of the Breast Surgery Fellowship at Massachusetts General Hospital, Brigham and Women s Hospital and the Dana-Farber Cancer Institute.

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JBCS/GBCC joint session: Best integration of supportive and palliative care in the continuum of breast cancer care

JSE-2-1-1Updated, Optimal Management of Febrile NeutropeniaDepartment of Oncology, Asan Medical CenterSung-Bae Kim

Febrile neutropenia remains an important complication of treatment with cytotoxic chemotherapy.

It is associated with life-threatening infections and may alter the chemotherapy schedule, thus impacting on early and long-term outcomes.Elderly breast cancer patients with impaired health status or advanced disease as well as patients undergoing dose-dense anthracycline/taxane- or docetaxel-based regimens have the highest risk of CIN. A careful assessment of the baseline risk for CIN allows the selection of patients who need primary prophylaxis with granulocyte colony-stimulating factor G-CSF and/or antimicrobial agents.

Specific risk assessment scores, along with comprehensive clinical evaluation, are able to define a group of febrile patients with low risk for complications who can be safely treated as outpatients. Conversely, patients with higher risk of severe complications should be hospitalized and should receive intravenous antibiotic therapy with or without G-CSF Selection of antibiotics should be based on the patient s symptoms, previous culture data, and institutional antibiograms. Ongoing therapy should be guided by culture and clinical data. Antimicrobial resistance is of great concern, particularly in this population, so careful attention to antibiotic selection The updated guideline includes the latest evidence on outpatient management of fever and neutropenia in adult patients undergoing treatment of malignancy. Guidance is provided to assist clinicians in identifying patients who may be candidates for outpatient management of fever and neutropenia, based on clinical criteria and/or validated scoring systems.

JSE-2-1-1Management of febrile neutropenia and optimal therapy with G-CSF for breast cancer patients in AsiaThe Cancer Institute Hospital of JFCRFumikata Hara

Breast cancer is mainly found as Curable disease. Therefore, it is important for breast care practitioners to carry out curative intent treatments and lead them to cure. Maintaining relative dose intensity

RDI of 85% or more is known to improve prognosis and decrease of RDI should be avoided as much as possible during chemotherapy. Febrile neutropenia FN is the most important cause of dose reduction, postponement and withdrawal, and FN management is very important for maintaining RDI. Pegfilgrastim is used for the purpose of preventing FN. In the use of G-CSF guidelines, primary prophylactic administration is recommended for FN high-risk regimens with more than 20% incidence.However, most of the clinical trials that underpin the incidence of FN were conducted in western countries, and even with the same chemotherapy regimen, the incidence rate of adverse events, especially, the hematologic toxicity is largely different between Western and Asian In particular, the incidence of FN in taxane regimens tends to be higher in Asians, including Japanese, than in Caucasian. While TC docetaxel, cyclophosphamide regimen frequently used for adjuvant adjuvant therapy has been reported to have an FN incidence rate of 4% in the US oncology 9735 trial, FN rate in the Japanese phase 3 trial was reported to be 68.8%. Therefore, FN prevention guidelines based on the risk of developing FN in Asians are considered necessary. Pegfilgrastim, on the other hand, allows for the use of a third-generation regimen such as dose dense chemotherapy or TAC, which has an increased therapeutic intensity, in addition to the benefit of maintaining RDI. The prognostic improvement is demonstrated in meta-analysis. It is necessary to confirm the effects and safety in Asia and to master the safety use.To avoid FN and maintain RDI and more intensive chemotherapy for recurrent high-risk cases by G-CSF for all breast practitioners will further improve breast cancer survival.

JSE-2-1-2Current management of lymphedemaDepartment of Surgery, Seoul National University College of MedicineWonshik Han

Lymphedema LE is a serious and common side effect of breast cancer surgery. Currently, it is estimated that 250 million people is living with lymphedema worldwide after breast cancer treatment. With the increasing use of sentinel lymph node biopsy and decrease in axillary lymph node dissection, incidence of LE is expected to decrease significantly. Current paradigm of LE treatment is early detection of subclinical and stage I LE and early intervention of mild LE. There have been supporting data that early swelling can be reversed with early intervention. However, there are controversies about diagnosis, def init ion, and assessment of LE. Recommended tools are circumference, perometry, and bioimpedance. Volume measures are not interchangeable and the incidence of LE is significantly dependent on the definition of LE. Among lifestyle factors suspected to be associated with LE, only sauna use was predictive in the study by Showalter et al Ann Surg Oncol 2013. In the studies by Ferguson et al J Clin Oncol 2016 and Asdourian et al J Clin Oncol 2017, Blood draws, injections, blood pressure measurement, and flying were not associated with incidence of LE, while cellulitis was associated with LE. Weight training and physical activity also are not associated with LE. For the management of LE, early referral to trained physician of patients at risk or the affected is important. For surgeons, practice of personalized surgery, RT, and use of genomic test to reduce unnecessary extensive treatments are best way to reduce LE incidence. For patients, maintaining healthy body weight, and encouraging exercise should be recommended.

JSE-2-1-2Patency Rate and Outcomes of Lymphaticovenous Anastomosis For Breast Cancer Related LymphedemaPlastic and Reconstructive Surgery, Faucalty of Medicine, Yokohama City UniversityJiro Maegawa

Introduction We have reported results in patency of lymphaticovenous side-to-end anastomosis LVSEA by lymphography and outcomes of combination of CDP and LVSEA in breast cancer-related lymphedema. The aim is to evaluate volume changes of the affected limbs and contents of CDP and patency of LVSEA.Methods Between 2009 and 2012 29 limbs of 29 patients with pre-and postoperative CDP and LVSEA were evaluated. All of them had breast cancer-related lymphedema. Volumes were calculated based on circumferential measurements at several points of the upper limb pre- and postoperatively. Moving average method was used for comparison of the volume at each period 100days. Patency of 119 anastomoses in the 29 patients was evaluated by ICG fluorescence lymphangiography after surgery with follow-up ranging from 5 to 51 months. We also asked the patients how they put or not compressive garments on the affected limb after surgery.Results The mean volume of the affected limb was 1232ml at the initial visit, 1173ml during 1 to 100 days before surgery, and 1146ml during 1 to 100 days after surgery. There were statistical difference between the volumes at initial visit and the mean of a 100-days period before surgery and between the mean volumes of a 100-days period before and after surgery. Out of 119 anastomoses 6151% were detectable. Out of 61 detectable sites 2643% were patent. Cumulative patency rate decreased gradually over the period of about 4 years. Regarding CDP, 14 patients became freed from putting the garments and contents of CDP were reduced in 11 after surgery.Discussion Although volume reduction was not much, about a half of the patients became freed from compression garments, which improved QOL of the patents so much. The patency rate of LVSEA in the upper limb lymphedema was similar to that in the lower limb lymphedema.Conclusions LVSEA is effective to reduce both volume of the affected limb and contents of CDP in the breast cancer related patients.

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JSE-2-1-3CINV1Breast Division, Department of Surgery, Samsung Medical Center 2Breast Division, Department of Surgery, Sungkyunkwan University School of Medicine 3Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan UniversityJeong Eon Lee1,2,3

It is very well known that Chemotherapy-induced nausea and vomiting CINV impairs quality of life and adherence to chemotherapy. According to the antiemetic guidelines, it is recommended that the prevention with optimal first-line antiemetic prophylaxis for acute and delayed CINV. However, several researches showed that adherence to guidelines is low, and antiemetics are often prescribed suboptimal ways. From the PrACTICE study to evaluate the burden of emesis in adults initiating highly emetogenic chemotherapy HEC or moderately emetogenic chemotherapy MEC regimens, it was reported that the management of CINV in cycle 1 of HEC in Korea should be more active in spite of the relatively higher rates than the Asia-Pacific AP region.There is recent a multicenter, randomized, double-blind study enrolled adult South Korean patients. Patients were randomized to a 3-day regimen of aprepitant or placebo control on top of ondansetron plus dexamethasone. The primary and key secondary efficacy endpoints were the proportions of subjects who achieved no vomiting and complete response CR during the overall phase. A 3-day aprepitant regimen was numerically better but not statistically superior to a control regimen in a non-AC MEC Korean population.There is another recent Korean study which is a randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of olanzapine for the prevention of CINV in patients receiving MEC. Although the complete response rates were not significantly different between the olanzapine and placebo groups, the percentage of patients with significant nausea and the use of rescue medications were lower in the olanzapine group.It is still on challenge to reduce the incidence of CINV and new compounds or combinations of knowns may improve quality of life. In this session, some recent published CINV studies on Korean population will be introduced.

JSE-2-1-3Development of the anti-emetic guideline in Japan1Division of Clinical Research Promotion, NHO Shikoku Cancer Center2Saitama Medical University3Fukuoka University4Todachuo General Hospital5Sapporo Medical UniversityKenjiro Aogi1Toshiaki Saeki2Kazuo Tamura3Keisuke Aiba4Kenji Okita5

In Japan, a number of clinical practice guidelines have been published since 2004 by several Japanese medical associations, including 83 organ-specific and 20 for supportive care, e.g. for pain control, the use of G-CSF, and anti-emesis. These guidelines show appropriate handling of medical problems in Japanese medical staff and contribute to better outcomes for cancer treatments. In particular, guidelines for supportive care and palliative care have shown clinical effectiveness through the appropriate coordination of cancer care. Chemotherapy-induced nausea and vomiting CINV is one of major complaints in patients with cancer who have received chemotherapy. In addition, good CINV treatment is one of factors that affect the good outcome of chemotherapy. Treatment with anthracyclines is one of standard chemotherapies for breast cancer patients, and should be adequately controlled by anti-emetic therapy. Therefore, clinical management of CINV in breast cancer patients has been a major obstacle to medical staff.The Japan society of clinical oncology JSCO published the anti-emetic guideline in 2010. This guideline has attracted considerable attention from medical professionals in Japan, including doctors, nurses and pharmacists. JSCO conducted an investigation into the penetration of the anti-emetic guideline for organizations participating in JSCO in 2012. In this survey, 586 51% were interested in the guideline, and 489 42.6 reported that they actually referred to it. Regarding the guideline-practice gap, the discrepancy between guideline recommendation and medical practice was investigated, and the reason was evaluated, and institutional clinical situation, domestic insurance application and preference of the patient and doctor were taken up. In order to improve the quality of the anti-emetic guideline, JSCO has organized the independent guideline-evaluating team. In addition, the Japanese anti-emetic guideline has been updated every 2 to 3 years to include new evidence, including the effectiveness of olanzapine in addition to standard therapy and steroid-sparing therapy. For effective supportive care for Japanese breast cancer patients, it is important to continuously improve the quality of the anti-emetic guideline.

JSE-2-1-4Early breast cancer and bone healthDepartment of Oncology, Asan Medical CenterJin-Hee Ahn

Treatments used for breast cancer can increase the risk of developing osteoporosis and the loss of bone strength make bones more fragile and prone to fracture. Cancer treatment-induced bone loss CTIBL significantly impact the quality of life of patients, and risk factors for osteoporosis-related fractures include aromatase inhibitor AI treatment, BMD T-score of 65, oral corticosteroid use for more than 6 months, low body mass index BMI

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JS-3-03-3Management of metastatic breast cancer - a thoracic surgeon s viewDepartment of Cardiac and Thoracic Vascular Surgery, University of Schleswig-Holstein, Luebeck Campus, GermanyBuntaro Fujita

Worldwide, breast cancer contributes about 25% of all new cancer cases in women. A substantial fraction of these patients will develop metastatic breast cancer MBC which is linked to poorer prognosis in most cases. MBC can affect all organs but mostly affects bones, lungs, brain and liver. The treatment strategy for MBC is always based on an individual patient base considering many prognostic factors such as patient age, tumor location, tumor biology, estimated life expectancy, prior treatment, comorbidities, patient preferences, progression free time intervals and many more. Optimal management of such patients is complex and requires the involvement of specialists from different fields which can comprise a clinical challenge. If MBC is suspected, thorough diagnostics including complete re-staging using imaging modalities CT, PET, scintigraphy, analysis of tumor markers as well as re-evaluation of the primary breast tumor are indispensable. Whenever possible, a biopsy of the metastatic tumor should be acquired to evaluate further relevant information on tumor biology and to rule out an additional primary tumor/benign tumor. Due to the complexity, patients with suspected MBC are increasingly discussed in interdisciplinary breast centers, which comprise all disciplines that are relevant for treatment of the individual patient. Such interdisciplinary discussions are important as the effect of surgical treatment of thoracic metastases are not well studied. Previous data suggest that surgical treatment of pulmonary MBC may prolong survival, but robust factors that predict long-term outcomes are not well defined. Rarely, MBC spreads to the heart and/or pericardium and experience with such patients is largely based on case reports making it difficult to formulate general recommendations for the treatment of such patients. This presentation will summarize current evidence regarding the diagnosis and patient selection for surgical therapy for thoracic MBC.

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JIS-1-01-1Overview

1987TCTLA-41992TPD-1James AllisonTTT2000TT20113CTLA-4FDAPD-12018PD-L1

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Barts Cancer Institute, Queen Mary University of London, UKPeter Schmid

JIS-1-01-3HER2++II

Background: Anti-PD-1 antibody has been developed for various cancer types including breast cancer. The synergic effect of combination of nivolumab, paclitaxel and bevacizumab has been anticipated based on various preclinical data. We initiated this investigator-initiated trial to evaluate the efficacy and safety of nivolumab + paclitaxel + bevacizumab therapy. Methods: This is a Phase II, multi-center, single-arm study to evaluate the efficacy and safety of nivolumab + paclitaxel + bevacizumab combination therapy as a first-line treatment for HER2-negative advanced metastatic or inoperable recurrent breast cancer. Patients will receive nivolumab + paclitaxel + bevacizumab until the protocol treatment is determined to be ineffective or may not be continued. The primary endpoint is the objective response rate ORR and key secondary endpoints include progression free survival, overall survival, and the toxicity of the protocol treatment. The threshold and expected ORR are 55% and 70%, respectively, and 47 patients are needed to ensure a statistical power of 80% =0.10. A total of 51 patients will be enrolled. Tumor t issue wi l l be evaluated for the TILs, PD-L1 expression, and gene expression analysis. Peripheral blood will be evaluated for immune s ta tus and cy tok ine profiling. This trial had opened to accrual on Feb. 2018 and completed accural on Oct. 2018. UMIN000030242.

JIS-1-01-4Development of immunotherapy for the patients with luminal and/or HER2 positive breast cancerMayo Clinic, Rochester MN USAMatthew P. Goetz

Immune checkpoint inhibitors including antibodies that target PD-1 and PD-L1 have demonstrated encouraging antitumor activity in triple negative breast cancer TNBC. The first FDA approval in breast cancer in regard to this class of molecules was recently announced with the drug atezolizumab, in combination with nab-paclitaxel, for the first-line treatment of metastatic PD-L1 positive TNBC Schmid NEJM 2018. Despite this success, the antitumor activity of immune checkpoint inhibitors in ER+/HER2 negative and HER2 positive breast cancer has been limited. In contrast, data from the neoadjuvant setting I-SPY2 demonstrated a high probability of success of a Phase III trial evaluating the addition of pembrolizumab when co-administered with neoadjuvant weekly paclitaxel followed by AC for high risk Mammaprint assay, ER positive, HER2-negative breast cancer Nanda 2017. In this talk, we will review some of the molecular features that may sensitize a subgroup of ER+/HER2 negative tumors as well as HER2+ tumors to immune checkpoint inhibitors. Furthermore, we will review ongoing and planned studies in the metastatic and adjuvant settings designed to assess the antitumor activity of immune checkpoint inhibitors in HER2+ as well as ER+/HER2 negative breast cancer.

228

JIS-1-01-5:

KEY DRUGPD-12PD-L12consolidation2nd-line1st-linedoubletPD-1, PD-L11st-line vs 2dn-line, vs

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JS-1-01-1Changing from radical mastectomy to nipple sparing mastectomy NSM1Surgery, Harvard Medical School2Breast Program, Massachusetts General Hospital3Division of Surgical Oncology, Massachusetts General HospitalBarbara L. Smith1,2,3

Breast cancer surgery has evolved in parallel with evolution in the understanding of breast cancer growth and metastasis. Radical mastectomy procedures developed when doctors believed that breast cancer spread out from the main mass, and that metastases remained connected to the primary cancer. It was thought that if the operation was big enough, the cancer could be cured. As we learned that breast cancer spread is embolic, mastectomies began to remove only breast tissue, and modified radical mastectomy or lumpectomy became standard. When breast reconstruction became possible, it was initially delayed until 1-2 years after mastectomy due to concerns that reconstruction might hide a recurrence. In the 1980 s immediate reconstruction was accepted, and skin sparing techniques were developed to preserve skin and improve cosmetic results. Studies showed that survival and risk of local recurrence at 10 years was the same for immediate skin sparing mastectomy as it was for delayed reconstruction or no reconstruction. Nipple preservation became desirable to improve cosmetic outcomes further. Subcutaneous mastectomies preserved the nipple but left 5-10mm of tissue under the areola to help blood supply. This approach was used for some prophylactic mastectomies but was not thought safe for cancer patients as some breast tissue was left under the areola. Recent anatomy studies of the nipple ducts and vessels show how to preserve the blood supply to the nipple and still perform careful removal of breast tissue in and under the nipple. Rates of nipple necrosis are low and recurrences in the nipple are very rare. Survival and local recurrence no different from skin sparing mastectomy in studies to date. Nipple sparing mastectomy is now standard at many institutions as it improves cosmetic results and often allows single stage implant reconstructions.

JS-1-01-2-- Exp.

Exp.Exp.111265retrospectiveExp.

JS-1-01-31212

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230

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SY-1-01-1New Insights into Endocrine Therapy Resistant Breast CancerLester and Sue Smith Breast Cancer, Baylor College of MedicineMatthew J. Ellis

The estrogen receptor positive subset is the dominant contributor to global deaths from breast cancer which now exceeds 500,000 deaths annually. The overall objectives of our research are to identify treatment-resistance drivers in ER+ breast cancer and to target their therapeutic vulnerabilities. Our discovery approach is to use DNA, RNA and peptide sequencing techniques to identify resistance drivers that can be subjected to mechanistic studies and therapeutic modeling. As sources of material we have analyzed includes both primary tumors that have been treated with neoadjuvant endocrine therapy, metastatic specimens and patient derived xenografts. These analysis have generated a number of new mechanistic hypotheses that relate resistance to endocrine agents to 1 specific defects in mismatch repair, 2 the generation of in-frame ESR1 gene fusion events, and 3 loss of the NF1 tumor suppressor gene Furthermore, the immunosuppressive microenvironment has a role to play in aggressive luminal B disease and subsets of these tumors will be sensitive to immune checkpoint therapy submitted. Finally, we are generating new proteogenomic tools that may provide better insights into the integrated effects of somatic mutations on the progression of ER+ disease as well as diagnosing therapeutic vulnerabilities.

SY-1-01-2

2017Center for Cancer Genomics and Advanced Therapeutics: C-CAT20182141110113561C-CAT20192146C-CATC-CAT

SY-1-01-3

SY-1-01-4

tumor mutation burden29 IDHSCRUM-Japanproof of concept

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236

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20042011National Clinical Database 132,24055646574753

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SY-1-05-1Pneumonitis: Not the end of cancer treatment

CTCT

EGFRm-TORCT

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SY-1-05-3Chemotherapy induced nausea and vomitingCINV1Princess Margaret Cancer Centre, Toronto2University of TorontoDavid Warr1,2

As a result of three decades of clinical trials, enormous progress has been made in the control of emesis due to breast cancer chemotherapy. By implementing evidence-based guidelines, vomiting and clinically important nausea can be prevented in a large majority of breast cancer patients receiving chemotherapy that contains cisplatin or an anthracycline plus cyclophosphamide. There is, however, a substantial gap between what is possible and what happens in practice. This talk will discuss 1 the impact of corticosteroids, 5-HT3 receptors antagonists, NK1 receptor antagonist and olanzapine, 2 barriers to optimal antiemetic therapy and 3 current controversies.

SY-1-05-4Why is prevention of neutropenia with G-CSF and other agents important?Genolier Cancer CenterMatti Aapro

Febrile neutropenia FN may be lethal. Granulocyte colony-stimulating factors G-CSFs can significantly reduce the risk of FN. International guidelines recommend G-CSF for patients receiving chemotherapy

ChT with FN risk of 20% or 10% to 20% with defined risk factors. Prophylaxis is not typically recommended for FN risk of

242

SY-1-05-5Anticancer treatment related Fatigue in Cancer Patients1 Integrated Cancer Rehabilitation Cancer Fatigue Clinic, Klinik Gais AG 2Clinic Medical Oncology and Hematology, Dept. Internal Medicine, Cantonal Hospital St.GallenFlorian Strasser1,2

Occurrence and severity.of cancer treatment related fatigue CtRF is often underrecognized. Diagnostic criteria include a history of fluctuating fatigue alineated to anticancer treatment cycles,later unusual profound fatigue poorly related to activities, sleep not helping to revocer fatigue, decreased attention span, concentration issues and memory problems. With emoty energy tanks, heavy limbs and sickness symptoms occur. Secondary depressive symptoms, loss of working ability and disability develop.

CtRF-mechanisms include dysregulation of inflammatory cytokines, hypothalamic regulation, serotonin and circadian melatonin secretion, mitochondrial muscle and nerve toxicity.

Risk factors for CtRF include pre-existing psychosocial distress or psychiatric disorders, chronic pain syndrome, lack of coping and physical activity resources, financial and social burden, and unhealthy eating habits.

CtRF screening applies symptom tools eg. ESAS in routine care, assessment adresses physical, emotional and cognitive fatigue issues e.g. SIF and CtRF impact on daily life eg. BFI.

Treatment for CtRF encompasses a multidimensional, transprofessional out- or inpatient rehabilitation approach including 1 endurance training, 2 mind-body-treatments e.g. Yoga, 3 protein-rich diet low in calories, 4 cognitive behavioural therapy enabling coping with reduced energy tanks, adapting expectations and changing habits, 5 approaching concious and unconcious emotions, existential distress and handicap grief, 6financial and insurance related support, and 7 reframing life goals and meaning.Later,longterm survivors merit repetitive monitoring for several years until stabilization.

Of crucial importance is acknowledgment of patients traumatization of not being heard in work, leisure, family and unfortunately, by many health care professionals. A first encounter being dominated by active listening is key for successful multimodal treatment.

SY-1-05-6 Cardio-Oncology 1231111112231

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5512.4stage/2168%stage/1032%2477%1135%LVEF 10%53%413%50.03.8SD vs 45.24.1 mm, P=0.0473 T0.024 IQR 0.02-0.29 vs 0.013IQR 0.009-0.017 ng/mL, P=0.0212QTc44533 vs 43220 msec, P < 0.01AMED20201812130CTRCDCTRCD6 CTRCD

SY-1-05-7

Onco-Cardiology

121Onco-Cardiology HER2ICIirAEICIirAEirAE

SY-1-05-8

3Oral Care-BC12345678Oral Care BC 912233445566778888891

MASCC 81%POC:Professional Oral Care320143262017122831174POC21:1POC8POC1681POC76.5%

62/8189.7%78/872 p=0.0352POC34.6%28/81 54%, 47 of 87 p= 0.015POC1822.2%28 32.2%POCPOC

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6

SY-1-06-1

2Cancer Cell 2011; Nat Commun 2012; Cancer Res 2013Oncogene 2010; Cancer Res 2019Zeb1Cdk4/6JBC 2012; Int J Cancer 2012

SY-1-06-2

EREMTTNBCERmTORPI3KEMTCDK

SY-1-06-3SERMFbxo22Luminal12345123452

Luminal Ki-67SERMSERMFbxo22Journal of Clinical Investigation, 2018SERMERSRC

N-CoRERKDM4BFbxo22 ERDNA SRCN-CoRAF-1 AF-2 AF-2 AF-1SRCSERMAF-2 SRCAF-1 SRCN-CoRKDM4B Fbxo22 Fbxo22SERMSRCChIPERSRC410ERSERMSRCFbxo22in vitroFbxo22MCF720052009ERHER2T2163Fbxo22Fbxo22p=0.0094:2.81Ki-67Ki-67Luminal A-likeFbxo22p=0.0056:3.91Validation p=0.0493:6.192Fbxo22Fo-22Oncotype DX

SY-1-06-4SNP array1234567891,4,51223,8336,974444444

hallmarkintratumor heterogeneity

genomic featuresER 10% / PgR10% LuminalLuminalnon-Luminal152SNPsLuminal5BRCA1CpG islandTP53PI3KCA

LuminalHigh-ChILow-ChIp=0.004HR+/HER2-p=0.046TP53Loss/UPD/mutationsBRCA1Normal+p

244

SY-1-06-5:1211111122

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SY-1-06-6ERpalbociclib

estrogen receptor ERmTORCDK4/6ERlineCDKpalbociclib

ER MCF7T47Dpalbociclib6 MCF7-PR, T47D-PRWestern bloteribulinERpalbocilibWST

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SY-1-06-7121112111

: tumor-infiltrating lymphocytes TIL : TIL : 1998 2017 127 14International Immuno-Oncology Working Group on Breast CancerTILTIL DCIS-TIL: TILDCIS-TIL 14.6%. 26%DCIS-TIL

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7

SY-1-07-1:JBCSWHO

18WHO12low grade carcinoma16q LOHlobular neoplasia CDH1 losssecretory carcinoma ETV6-NRTK3 fusion geneadenoid cystic carcinoma MYB-NF1B fusion geneinvasive ductal carcinoma solid typeBRCA1 dysfunction3invasive ductal carcinoma scirrhous typeinvasive carcinoma with fibrotic focusinvasive ductal carcinoma solid typemedullary carcinomatumor infiltrating lymphocytesJBCSWHO

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2012WHO4201261717WHO2018518WHOWHO42018ERPgRHER2MIB-110%"?""Background Question BQ"20181 2 3 4 5 6

SY-1-07-3 Mammary carcinomas with neuroendocrine features12341,32,3444

NECWHO42012NETNE1NET2NEC/3NE182018NE50%chromogranin AsynaptophysinLCNECWHO1%5%Preinvasive counterpartNE-DCISref. solid papillary carcinomadivergent differentiationNENETs"" luminal phenotype NET/NECTips & Traps;https://researchmap.jp/read0145980/

SY-1-07-4 tumor -infiltrating lymphocytes 1211121

TILs TILs>50% >60% TILs LPBC TNBCHER2 HR 20%16%6%TNBCHER2TILTILs1HETILs s-TILs TILs 2017 s-TILsTILs i-TILs hot spot s-TILs80%80% s-TILsCD3, CD8 "Immunoscore" TNMTILsTILs

246

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WHOintraductal proliferative lesions-TDLUUDHcolumnar cell lesions

FEAADHDCISUDHDCISDCISDCISUDHDCISDCISADHDCIS2mmADHFEAADHFEA

SY-1-07-6Fibroepithelial neoplasm

fibroepithelial neoplasms of the breastfibroadenomaphyllodes tumorWHO3desmoid-type fibromatosismediator complex subunit 12 MED12TERT promoter

247

8Augmented Intelligence

SY-1-08-1Society 5.0

Society 5.0SHIROKANE20157IBM Watson for Genomics38Watson for Genomics5

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249

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SY-1-09-1

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251

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11HER

SY-2-11-1HER2-negative HR-positive advanced breast cancerDepartment of Clinical Medicine and Surgery, University of Naples Federico IIGrazia Arpino

Improved knowledge about the complex biology of hormone receptor-positive HR-positive breast cancer and mechanisms of resistance to endocrine therapy has led to a dramatic increase in treatment options in this setting. For instance, in patients with HR-positive metastatic breast cancer MBC, there are now an unprecedented number of endocrine-based therapies that can improve long-term outcomes, preserve quality of life, and delay the use of chemotherapy. In addition to antiestrogens and steroidal and nonsteroidal aromatase inhibitors, the selective estrogen-receptor degrader, fulvestrant, and the new endocrine-based combinations with CDK 4/6 inhibitors and PI3K/mtor inhibitors have further improved the outcomes in the first line setting and beyond. However, the optimal sequencing of all these therapies remains unclear. This overview will describe mechanisms of action and resistance to different endocrine agents and discuss current and investigational approaches to sequential single-agent endocrine and endocrine-based combination therapy for the long-term management of patients with HR-positive, human epidermal growth factor receptor 2-negative MBC.

SY-2-11-2Selective Estrogen Receptor Down regulatorSERDUniversity of Nottingham, Graduate Entry Medical School, University Hospitals of Derby & Burton NHS Foundation TrustJohn Robertson

George Beatson first reported oophorectomy in 1896 in the treatment of a patient with advanced breast cancerABC. Subsequently, reducing the blood levels of circulating estrogens in postmenopausal women by way surgical adrenalectomy- and later aromatase inhibition - were also found to induce responses in breast tumours. In 1958 Elwood Jensen discovered the estrogen receptor ER and since then ER and the cellular pathway it regulates have been a focus of expanding research: one area has been drugs which block estrogen binding to ER ie anti-estrogens. Tamoxifen TAM was the first anti-estrogen reported in the treatment of patients with ABC in 1971 and approved in UK in 1973 & USA in 1977. TAM was the first of a class of drugs called Selective Estrogen Receptor Modulators SERMs which can act as antagonists of the ER in breast cancers but also have partial agonist properties on other organs eg bone, endometrium. In the 1990s and 2000s there was an explosion of interest in newer designer SERMs but none of these proved better than tamoxifen and none were effective after TAM ie they were cross-resistant.Selective Estrogen Receptor Downregulators SERDs were a new class of drug. Initially introduced through clinical trials over 25 years ago, fulvestrant Faslodex was approved in 2002 as second line therapy after TAM. By this fact alone- ie it was not cross-resistant to TAMthe SERD separated itself from all the SERMs. By 2000, the 3rd generation aromatase inhibitors AIs, anastrozole, anastrozole & exemestane, had overtaken TAM as the endocrine therapy of first choice. Subsequent research FIRST & FALCON trials has shown fulvestrant 500mg is also more efficacious than anastrozole in hormone nave patients. Due to short patent life fulvestrant 500mg has not been developed in the adjuvant setting. However FIRST & FALCON have set the scene for the current, ongoing programmes by a number of pharmaceutical companies to develop 2nd generation oral SERDs.

SY-2-11-3Exploratory analyses of PIK3CA and ESR1 mutations in early and late stage breast cancer from neoMONARCH and MONARCH 21Kyoto University, Kyoto, Japan2Stanford University, Stanford, CA3Saitama Cancer Center, Saitama, Japan4NHO Osaka National Hospital, Osaka, Japan 5Instituto de Investigacion Sanitaria Gregorio Maraon, Ciberonc, Geicam, Universidad Complutense, Madrid, Spain6Dana-Farber Cancer Institute, Boston, MA, USA7Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg, Leuven, Belgium 8Dartmouth-HitchcockMedical Center, Lebanon, NH, current institution University of Vermont9Eli Lilly and Company, Indianapolis, IN, USA10University of California, Los Angeles, CA

Masakazu Toi1George W. Sledge, Jr.2Kenichi Inoue3Norikazu Masuda4Miguel Martin5Sara Tolaney6Patrick Neven7Peter A. Kaufman8Lacey M. Litchfield9Sameera Wijayawardana9Valerie M. Jansen9Sara Hurvitz10Dennis Slamon10

Combination treatments of CDK4 & 6 inhibitors CDK4 & 6i with endocrine therapy ET have improved outcomes in patients with HR+ advanced breast cancer ABC. Abemaciclib is a selective inhibitor of CDK4 & 6 approved on a continuous dosing schedule for the treatment of HR+, HER2- ABC, alone or in combination with ET. Aside from hormone receptor status HR+, no predictive biomarker of clinical benefit from CDK4 & 6i has been identified. This study evaluated the PIK3CA and ESR1 mutation mut status in early-stage and ABC from the neoMONARCH NCT02441946 and MONARCH 2 NCT02107703 studies of abemaciclib, respectively. DNA from baseline FFPE tumor samples from neoMONARCH n=200 and MONARCH 2 n=434 and baseline plasma samples from MONARCH 2 n=334 were analysed by droplet digital PCR for 4 hotspot muts of PIK3CA E542K; E545K; H1047L; H1047R and ESR1 D538G; Y537C; Y537N; Y537S. Samples that failed DNA QC or those with undetermined mut status were excluded from analysis. PIK3CA muts were detected in 34.2% 52 of 152 of FFPE samples from neoMONARCH and 39.9%

133 of 333 of FFPE and 40.3% 96 of 238 of plasma samples from MONARCH 2. The concordance of PIK3CA muts in ctDNA and FFPE samples was 62.8% in MONARCH 2. ESR1 muts were detected in 5.1%

8 of 156 of FFPE samples from neoMONARCH and 4.4% 15 of 344 of FFPE and 64.4% 190 of 295 of plasma samples from MONARCH 2. The concordance of ESR1 muts in ctDNA and FFPE samples was 37.1% in MONARCH 2. The low detection rate of ESR1 muts in FFPE samples from the 2 studies can be explained in part by the biopsy site - primary vs metastatic. In neoMONARCH, PIK3CA mut status had no effect on Ki67 expression change from baseline to 2 weeks in response to abemaciclib alone or in combination with anastrozole ANZ, compared to ANZ alone. In MONARCH 2, median PFS was improved in abemaciclib plus fulvestrant F compared to placebo plus F regardless of PIK3CA or ESR1 mut status in ctDNA PIK3CA wild-type WT - 20.0 vs 12.7 mos, hazard ratio HR, 95% CI: .68, .42-1.09; PIK3CA mutant - 15.0 vs 5.7 mos, HR, 95% CI: .46, .27-.78; ESR1 WT - 16.3 vs 11.6 mos, HR, 95% CI: .69, .41-1.18; ESR1 mutant - 21.9 vs 10.3 mos, HR, 95% CI: .49, .33-.73; however, the benefit was numerically greater for patients with tumors harboring muts in PIK3CA/ESR1. These findings may inform which tumors may benefit most from abemaciclib therapy.

SY-2-11-4Immune effects of CDK 4 and 6 inhibitors in breast cancer and prospects for combination therapy with checkpoint inhibitorsMayo Clinic; Rochester, MN USAMatthew P. Goetz

Pharmacologic inhibitors of CDKs 4 and 6 CDK 4/6i have changed the treatment landscape for breast cancer. Although this class of molecules was developed to inhibit tumor cell proliferation, there are increasing data that CDK 4/6i have diverse effects on both cancer cells and the tumor microenvironment. Of particular note is the observation that CDK 4/6i can enhance tumor cell immunogenicity by increasing cancer cell presentation of tumor neoantigens on major histocompatibility complex MHC class I molecules Goel, Nature 2017. Additionally, CDK 4/6i increase tumor infiltration and activation of effector T cells and are able to augment the response to PD-1 blockade Deng, Cancer Discovery 2018. We will review the preclinical data surrounding the immune effects of CDK 4/6 inhibitors, both alone and in combination with checkpoint inhibitors, and discuss the ongoing and planned studies for the combination of immune checkpoint inhibitors and CDK 4/6i in breast cancer.

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SY-2-11-5TNBC: Novel StrategiesNorthwestern University; Robert H. Lurie Comprehensive Cancer CenterWilliam J. Gradishar

Breast cancer therapeutics have evolved from treating a single disease to subtypes based on expression of markers ER, PR and HER2 that can be assessed with immunohistochemistry or more sophisticated tests to molecular subtyping that can define specific abnormalities that can be targeted with novel agents or immunotherapies. The refinement of our ability to rigorously define the specific subtype of breast cancer in a given patient allows clinicians to tailor therapy with improved clinical outcomes. This approach has taken root in the metastatic disease setting but as results have been validated, tailored approaches have also been applied in the adjuvant and neo-adjuvant setting.

One of the largest challenges facing clinicians is improving outcomes for patient with TNBC ER/PR/HER2-negative disease. Until very recently the only option for treatment was chemotherapy. With the introduction of PARP inhibitors for those patients BRCA-mutated tumors another option became available, but only a minority of patients benefit. Similarly, the enthusiasm for immunotherapy as a cancer therapy realized its potential in several malignancies such as melanoma and lung cancer, but the development lagged in breast cancer until recently. Now, a large clinical trial in metastatic TNBC demonstrated a clear clinical benefit to those patients receiving a checkpoint inhibitor plus chemotherapy compared to chemotherapy alone. In another effort to define which subset of patients truly benefit from the addition of the checkpoint inhibitor, translational work determined that only those individuals with tumors that are PDL1+ gained benefit. As a result, clinicians can be more precise in their recommendations for this type of therapy and use it earlier in the algorithm of treatments of metastatic disease.

Additional strategies are being investigated for TNBC including the development of antibody -drug conjugates ADC that target specific antigens on tumor cells allowing more precise delivery and internalization of the cytotoxic agent to the tumor cell. Several agents are far along in development with registration trials complete in some. The promise of this strategy is not only more precise targeting of tumor cells but less toxicity experienced by the patient.

These topics along with updates from the 2019 ASCO meeting as it relates to TNBC in both early and late stages will be discussed

SY-2-11-6Molecular analysis and treatment of metastatic triple negative breast cancerBreast Cancer Prevention Research, Texas Oncology, Baylor University Medical CenterJoyce A. OShaughnessy

Triple negative breast cancer is comprised of a heterogeneous group of diseases with a broad range of sensitivity to standard chemotherapy. Intensive efforts to subclassify TNBC are underway including PAM50 intrinsic subtyping, the Vanderbilt, Baylor and Fudan University gene expression profiling systems, as well as classification based on predicted sensitivity to DNA damaging cytotoxic therapy, checkpoint inhibitor therapy and androgen receptor AR inhibition. To date, none of the TNBC subtyping systems have been validated such that they are of clinical utility in standard practice for patients with early stage or metastatic disease. In addition to prognostic and predictive TNBC subtypes defined by gene expression profiling, therapeutic targets are of high interest in subclassifying TNBC. Recently PD-L1 expression on stromal infiltrating immune cells was shown to identify 40% of metastatic TNBC patients who benefited from atezolizumab, an anti-PD-L1 monoclonal antibody, added to first-line nab paclitaxel chemotherapy. PD-L1 expression is the first tumor-specific predictive marker outside of ER, PR and HER2 to be validated in a prospective phase III trial, and assessing PD-L1 is a new diagnostic standard of care for newly diagnosed metastatic TNBC patients. Evaluating germline BRCA1/2 status is also a standard of care for metastatic TNBC patients because of the proven utility of the PARP inhibitors, olaparib and talazoparib, in treating gBRCA-positive HER2-negative metastatic breast cancer patients. Several other therapeutic targets are being evaluated in ongoing TNBC clinical trials including AKT, PIK3CA, PTEN and AR. Activation of AKT/PI3K is critical to the survival of TNBC, and two AKT inhibitors, ipatasertib and capivasertib, have shown promise in inhibiting this pathway in molecularly-selected metastatic TNBC patients in phase II trials. Phase III trials of these agents are underway in patients with genomic alterations in AKT, PI3K or PTEN. Likewise, early trials have shown that bicalutamide and enzalutamide are effective in blocking AR activity in patients with high AR-expressing metastatic TNBC. Somatic mutations in BRCA1/2 and germline mutations in other DNA repair genes such as PALB2, CHEK2, ATM, etc are being evaluated as potential targets for PARP inhibitors in ongoing clinical trials.

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12HER

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HER2TDP

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HER2MBCTDP

SY-2-12-6Role anti Her-2 therapy in metastatic setting for breast cancer1German Breast Group; Germany2Goethe University Frankfurt; Germany3Centre for Haematology and Oncology Bethanien, Frankfurt; GermanySibylle Loibl1,2,3

Although treatment for metastatic HER2+ breast cancer has been improved and survival could be extended extensively, cure is still not possible. However, many treatment options are available and therapy is in many ways fairly standardised. Based on the data of the Cleopatra study the dual anti-HER2 blockade using trastuzumab plus pertuzumab in addition to docetaxel has become standard of care for first-line treatment in metastatic HER2+ breast cancer. Other taxane have been investigated in the PERUSE study and confirm feasibility. Second line therapy consists in gerneral of T-DM1 an anti-body drug conjugate which demonstrated its superiority compared to capecitabine plus lapatinib after failure of trastuzumabEmilia study and in further lines compared to treatment of physicians choice THERESA study. Thereafter several combination therapies with trastuzuamb plus chemotherapy or lapatinib can be used. Earlier studies demonstrated that it seems of benefit to continue anti-HER2 therapy as long as treatment is indicated. The Pernetta study investigated whether a chemo-free treatment using dual-anti HER2 therapy aloene or in combination with endocrine therapy in case of HR-positivity is as effective as the the dual-therapy with paclitaxel or vinorelbine, in both arms followed by T-DM1. OS was not different at 3 years. The use of additional endocrine therapy in combination with anti-HER2 therapy after chemotherapy initiation seems to improve PFS. New drugs are currently in clinical trials, e.g. neratinib pan TKI targetting the EGFR family, new antibody drug conjugates with new linker and payload are currently in phase III clincial trials. The role of additional targetted drugs, such as immune checkpointinhibitors or CDK4/6 inhibitors is also further investaged.

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31NGSNGS PanelFoundation One CDxNCC-OncopanelNGS Panel20127NCC OncopanelTOP-GEAR Trial of Onco-Panel for Gene-profiling to Estimate both Adverse events and Response by cancer treatment NCC-Oncopanel75%Actionable DrugsActionable DrugsPIK3CABRCA1/2AKTBRAFESR1CCND1ERBB2FGFRCDK4NGS Panel30%Actionable DrugRRCBR13%27%Real WorldNGS PanelPDL1, PI3K, PARPNGS Panel NCC-Oncopanel

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SY-2-14-1Proteogenomics of Claudin-Low Breast Cancer1Lester and Sue Smith Breast Cancer, Baylor College of Medicine 2Department of Breast Surgery, Shizuoka Prefectural Hospital Organization, Shizuoka General HospitalMatthew J. Ellis1Ryoichi Matsunuma2

To illustrate our approach to therapeutic target discopvery we will describe a Clinical Proteomic Tumor Analysis Consortium CPTAC proteogenomic analysis that prioritized dihydropyrimidinase-like-3

DPYSL3 as a multilevel RNA/protein/phosphoprotein expression outlier specific to the claudin-low CLOW subset of triple-negative breast cancer. A PubMed informatics tool indicated a paucity of data in the context of breast cancer, which further prioritized DPYSL3 for study. DPYSL3 knockdown in DPYSL3-positive DPYSL3+n CLOWcell lines demonstrated reduced proliferation, yet enhanced motility and increased expression of epithelial-to-mesenchymal transition EMT markers, suggesting that DPYSL3 is a multifunctional signaling modulator. Slower proliferation in DPYSL3-negative DPYSL3CLOW cells was associated with accumulation of multinucleated cells, indicating a mitotic defect that was associated with a collapse of the vimentin microfilament network and increased vimentin phosphorylation. DPYSL3 also suppressed the expression of EMT regulators SNAIL and TWIST and opposed p21 activated kinase 2

PAK2-dependent migration. However, these EMT regulators in turn induce DPYSL3 expression, suggesting that DPYSL3 participates in negative feedback on EMT. In conclusion, DPYSL3 expression identifies CLOW tumors that will be sensitive to approaches that promote vimentin phosphorylation during mitosis and inhibitors of PAK signaling during migration and EMT.

SY-2-14-2121,2

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SY-2-14-3

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SY-3-17-1Genomic Testing to Optimize Decision-Making and Improve Outcomes for Early Stage Breast Cancer

ESBCMedicine Weill Cornell Medical College, Memorial Sloan Kettering Cancer CenterAndrew D. Seidman

Given a proliferation of gene assays and unique biomarker profiling, it is important to critically assess their obvious and often subtle differences. The specific context for the proposed use, analytic validity, clinical validity, and clinical utility must all be examined to appropriately employ available assays in alignment with the pertinent clinical management issue to be addressed.In order to optimize recommendations on appropriate use of breast tumor marker assays to guide decisions on adjuvant treatment for ESBC, evidence-based guideline recommendations were generated via literature search and prospectively defined study selection of systematic views, meta-analyses, randomized controlled trials, prospective-retrospective studies, and published prospective randomized trials

1. In addition to estrogen and progesterone receptors ER and PR and HER2, sufficient evidence of clinical utility was found for Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, and urokinase plasminogen activator and plasminogen activator inhibitor type I in specific subgroups of ESBC. Many assays offer prognostic power; only one assay - Oncotype DX - has demonstrated the ability to predict chemotherapy benefit in ER+/HER2-, node negative BC 2. No biomarker except for ER, PR and HER2 were found to guide choices of specific therapy. Assays performed on the same tumor tissue may yield discordant prognostic information 3, and the performance of multiple prognostic assays on the same specimen should be avoided.References:1. Krop I, Ismaila N, Andre F et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. J Clin Oncol 3524:2838-47, 20172. Sparano JA, Gray RJ, Makower DF et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med 3792:111-21, 20183. Varga Z, Sinn P, Seidman AD. Summary of head-to-head comparisons of patient risk classifications by the 12-gene Recurrence Score RS assay and other genomic assays for early breast cancer. Int J Cancer 2019 Jan 17. Doi: 10.1002/ijc.32139.

Epub ahead of print

SY-3-17-2Curebest 95GC

Curebest 95GC95GCER/n-549ER/n-training set95GC2High/Low

95external validation setn=459ER/HER2/n-/P=5.5e-10high risklow risk95GCOncotype DX21GCRecurrence Onlin:http://www.recurrenceonline.com21GCintermediate risk2

P=0.002BCRT 2013high risklow riskPaclitaxel-FECpCR17.9% vs 3.6%Cancer Lett 201295GC54000CEL fileCEL file 23GCNAC Ann Oncol. 201442GC BCRT 2018155GCNAC Cancer Lett 2015DATADATA95GCFFPERecurrence score

SY-3-17-3Genetic tests to predict breast cancer recurrence risk-Updates on Mammaprint in clinical practiceDepartment of Clinical Medicine and Surgery, University of Naples Federico IIGrazia Arpino

In the last decade, the use of genomic tests to determine the risk of recurrence in early-stage breast cancer has increased substantially. Gene expression signatures categorize breast cancers into subtypes with increased biological homogeneity, supporting a more personalized approach to disease management than conventional clinicopathological factors. MammaPrint Agendia NV, the Netherlands examines the expression levels of 70 genes to assess the risk of distant metastasis in breast cancer and classifies tumors as high vs. low risk. In the adjuvant setting, the quality of prognostic classification by MammaPrint has been evaluated in several retrospective and prospective studies. The prospective, randomized, international MINDACT trial Microarray in Node Negative and 1 to 3 Positive Lymph Node Disease May Avoid Chemotherapy

EORTC 10041/BIG 304 randomized patients with discordant risk classification by clinical vs. MammaPrint risk assessment into groups treated according to one or the other classifications. In particular, 5-year distant metastasis-free survival 5y-DMFS was 95% in the clinically high-risk group randomized to receive no chemotherapy due to low-risk MammaPrint classificationthus achieving the primary endpoint lower confidence limit > 92%.The MammaPrint test is recommended by national and international guidelines to support adjuvant therapy decisions and is currently used in daily practice. In the present overview we will review the data supporting the evidence of clinical utility of this test and its impact on systemic adjuvant chemotherapy decisions in hormone receptor HR-positive HER2-negative breast cancer.

SY-3-17-4Triple Negative Breast Cancer and genomic medicineDepartment of Breast Medical Oncology, The University of Texas MD Anderson Cancer CenterNaoto T. Ueno

The latest technologies allow classifying triple-negative breast cancer TNBC into various molecular subtypes. Protein, RNA, and DNA analyses can yield lightly different classifications. However, increased understanding of TNBC s molecular changes has only led to one drug a PARP inhibitor gaining FDA or PMDA approval. The challenge that we face is how to classify TNBC based on clinically relevant outcomes so that we can predict response to a specific drug. In contrast, in hormone receptor-positive breast cancer, genomic medicine has allowed prognostication leading to optimal selection of patients for new drug treatments.

In patients with TNBC, poor outcomes result from recurrent disease owing to metastasis. Metastasis may occur in part from the resistance of TNBC to therapy, which can be classified into three types: 1 intrinsic resistance owing to molecular characteristics present before chemotherapy is initiated, 2 adaptive resistance owing to molecular changes soon after chemotherapy is initiated, and 3 acquired resistance as indicated by residual or recurrent disease after prolonged chemotherapy. Most likely, all three types of resistance contribute to a lack of pathologic complete response to preoperative chemotherapy in TNBC patients.

The University of Texas MD Anderson Cancer Center has launched the Breast Cancer Moon Shot program, an unprecedented effort to dramatically accelerate the pace of converting scientific discoveries into clinical advances that reduce TNBC deaths. The Moon Shots Program is built on a "disruptive paradigm" that brings together the best attributes of both academia and industry by creating cross-functional teams working in a goal-oriented, milestone-driven manner to convert knowledge into tests, devices, drugs, and policies that can benefit patients as quickly as possible.

The learning objective of this talk is to provide our comprehensive review based on the current knowledge of molecular changes in TNBC and to describe how the Moon Shots Program has impacted the TNBC research over the past 5 years.

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SY-3-17-5RNA profiling for Breast Cancer, Does Technology Matter?Lester and Sue Smith Breast Cancer, Baylor College of MedicineMatthew J. Ellis

As the competitive landscape of RNA profiling tests for breast cancer evolves, issues of accessibly, accuracy and reimbursement have come to the fore. There seems very little question regarding the appropriateness of de-escalation of therapy in low risk ER+ node negative disease. Multiple algorithms and testing scenarios exist to safely deescalate therapy in this setting, mostly because the at-risk population already had a low risk as on staging, and so the consequences of a genomic miss-diagnosis is low. For node positive breast cancer, safe de-escalation is a more complex question. Patients do not have a good prognosis, yet outcomes may not be improved by chemotherapy. Here, chemotherapy, as opposed to endocrine monotherapy, is clearly a nuanced decision, particularly in populations with node positive yet low grade or lobular cancer. In this presentation, the issue of treatment escalation in node positive disease will be discussed with an emphasis on molecular tests that could be useful in this setting.

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18Curing Metastatic Breast Cancer

SY-3-18-1121122

PET/CTDNA

circulating tumor DNA;ctDNAcirculating tumor cell;CTCPET/CTFDG-PET/CTCTCPET/CTPET/CTPETF-18DiagnosisTherapeuticsTheranosticsPETLu-177Radio-ligand therapy

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Curable IncurableStageIVCurable+IncurableStageIVvisceral crisisQOLcurableStageIVOligometastasisOSoverall survivalDFSdisease free survival StageIIIB,IIICpCRDFS85%7.2StageIVOSDFSCure

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SY-3-18-5Generating Large Numbers of Exceptional Responders. Immunotherapeutic Approaches.

exceptional responder NCI s Exceptional Responder Study

NCT02243592 20192 Tumor Infiltrating Lymphocyte; TILProgrammed cell Death 1- Ligand 1 PD-L1 Tumor Mutation Burden; TMB non-responder responder TTIL

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12/heterogeneity10%TIL/MSI/Tumor Mutation BurdenBRCAness/HRDscorePD-L1

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QOLDr. HortobagyiOligo-metastasesCRcureBiologyCureHER2HER2BRCAPARPHRCDK4/6Heterogeneitytumor burden QOLExceptional RespondersCure

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51091.1%79.3%

2 / shared care,

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1. Shapiro CL: Cancer Survivorship. N Engl J Med 37925: 2438-2450, 20182. Takahashi M: Psychosocial distress among young breast cancer survivors: implications for healthcare providers. Breast Cancer 216: 664-669, 2014

SY-3-19-2Care for Breast cancer survivors in the EU1 Integrated Cancer Rehabilitation Cancer Fatigue Clinic, Klinik Gais AG 2Clinic Medical Oncology and Hematology, Dept. Internal Medicine, Cantonal Hospital St.GallenFlorian Strasser1,2

Cancer survivorship is an increasing topic in European healthcare. Patients numbers increase due to ageing, effectiveness of anti-cancer treatments and secondary prevention. Several initiatives cover post-curative survival issues both in the first few years after anti-cancer treatment and in long-term survivorship late adverse events, long-term disability, recurrence of primary cancer and secondary neoplasms.

Currently, there is a need to further develop guidelines and recommendations for evidence based tools to prevent or treat mid-term as long-term complications in the physical, mental, psychosocial and work-place areas, tailored to the variability of European countries: different models of medical oncology, general practitioners, centralized or more regional care, nursing care, patient advocacy groups and national cancer leagues.

Several initiatives are promising examples.Euro Donna is an european-wide advocacy network.European Society of Medical Oncology offers a patient guide on survivorship in cooperation with the European Cancer Patient Coalition. EORTC tackles childhood survivorship care.Synergistic expertise from specialists and oncologists is promising, such as Cardio-oncology or Psycho-oncology e.g. Fear-of.Recurrence, Several digital tools are under development e.g. detection of colorectal cancer recurrence.

Cancer rehabilitation is developping, evaluating and offering services for cancer survivors post-surgery, post-radiotherapy and post-systemic anti-cancer treatments, both for coordinated ou