Audio and slides for this presentation are available on YouTube: http://youtu.be/ozNSEND5PbE
Erica Mayer, MD, MPH, of the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, discusses triple-negative breast cancer and what makes it different from other forms of breast cancer. Mayer also talks about treatment options for triple-negative breast cancer and what you need to know about clinical trials for the disease.
Randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor positive (HR+) early breast cancer (BC):
The Changing Role of PARP Inhibitors in the Treatment of Ovarian Cancerbkling
In recent years, researchers have been looking into using a class of drugs called PARP inhibitors to prevent the progression and recurrence of ovarian cancer. Dr. Kathleen Moore of Stephenson Cancer Center, Principal Investigator of the SOLO-1 trial, explains how the results of this trial may affect ovarian cancer patients and where research on ovarian cancer treatment is headed next.
Report Back from San Antonio Breast Cancer Symposium (SABCS 2022)bkling
Curious about the latest developments in Early-Stage Breast Cancer and Metastatic Breast Cancer Research? Join us as Dr. Anne Blaes, the Division Director of Hematology/Oncology/Transplantation and Professor in Hematology/Oncology at the University of Minnesota, breaks down the most recent developments released at the annual San Antonio Breast Cancer Symposium regarding early-stage and metastatic breast cancer research.
Audio and slides for this presentation are available on YouTube: http://youtu.be/ozNSEND5PbE
Erica Mayer, MD, MPH, of the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute, discusses triple-negative breast cancer and what makes it different from other forms of breast cancer. Mayer also talks about treatment options for triple-negative breast cancer and what you need to know about clinical trials for the disease.
Randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor positive (HR+) early breast cancer (BC):
The Changing Role of PARP Inhibitors in the Treatment of Ovarian Cancerbkling
In recent years, researchers have been looking into using a class of drugs called PARP inhibitors to prevent the progression and recurrence of ovarian cancer. Dr. Kathleen Moore of Stephenson Cancer Center, Principal Investigator of the SOLO-1 trial, explains how the results of this trial may affect ovarian cancer patients and where research on ovarian cancer treatment is headed next.
Report Back from San Antonio Breast Cancer Symposium (SABCS 2022)bkling
Curious about the latest developments in Early-Stage Breast Cancer and Metastatic Breast Cancer Research? Join us as Dr. Anne Blaes, the Division Director of Hematology/Oncology/Transplantation and Professor in Hematology/Oncology at the University of Minnesota, breaks down the most recent developments released at the annual San Antonio Breast Cancer Symposium regarding early-stage and metastatic breast cancer research.
Introduction to Targeted Therapies in OncologyMohamed Abdulla
Describes the molecular background which represents the core for developing targeted therapies against specific biological events in malignant cellular clones.
Audio and slides for this presentation are also available on YouTube: http://youtu.be/ukXhuy5cXrE
Huma Q. Rana, MD, a cancer geneticist with Dana-Farber Cancer Institute, explains the cancer risk associated with BRCA1 and BRCA2 gene mutations. This presentation was originally given on July 23, 2013 as part of the "What Every Woman Should Know" event put on by Dana-Farber's Susan F. Smith Center for Women's Cancers.
It describes the prevalence of Breast Cancer among BRCA 1/2 mutations with special consideration to biological background, detection and screening, actions taken upon discovering mutation carriers and whether we have a different therapeutic algorithm than sporadic cases. Special emphasis on the role of PARP inhibitors in the management of metastatic disease.
What are the latest treatment advances for HER2-positive metastatic breast cancer? Eric Winer, MD, director of the Breast Cancer Program in the Susan F. Smith Center for Women's Cancers, discusses some of the latest research and treatment options.
This presentation was originally given as part of the 2015 Metastatic Breast Cancer Forum, held on October 17 at Dana-Farber Cancer Institute in Boston, Mass.
For more information, visit www.susanfsmith.org
Breast Cancer Treatment: Where we are, Where we're going - April 24th, 2018Summit Health
Summit Medical Group MD Anderson Cancer Center Lecture Series. A lecture and panel discussion format about the latest advances in surgery and innovative therapies for breast cancer presented by Summit Medical Group MD Anderson Cancer Center Specialists Dr. Lisa Mills, Dr. David Schreiber and Dr. Winnie Polen.
Please share this webinar with anyone who may be interested!
Watch all our webinars: https://www.youtube.com/playlist?list=PL4dDQscmFYu_ezxuxnAE61hx4JlqAKXpR
Cancer care is increasingly tailored to individual patients, who can undergo genetic or biomarker testing soon after diagnosis, to determine which treatments have the best chance of shrinking or eliminating tumours.
In this webinar, a pathologist and clinical oncologist discuss:
● how they are using these new tests,
● how they communicate results and treatment options to patients and caregivers, and
● how patients can be better informed on the kinds of tests that are in development or in use across Canada
View the video: https://youtu.be/_Wai_uMQKEQ
Follow our social media accounts:
Twitter - https://twitter.com/survivornetca
Facebook - https://www.facebook.com/CanadianSurvivorNet
Pinterest - https://www.pinterest.com/survivornetwork
YouTube - https://www.youtube.com/user/Survivornetca
Strategies for Managing Recurrent Ovarian Cancerbkling
When ovarian cancer returns, it's not uncommon to experience a range of emotions and feel overwhelmed. But it's important to remember that recurrent ovarian cancer can often be successfully treated. Dr. Shannon N. Westin, gynecologic oncologist and clinical investigator at MD Anderson Cancer Center, goes over the latest treatment options for recurrent disease.
Introduction to Targeted Therapies in OncologyMohamed Abdulla
Describes the molecular background which represents the core for developing targeted therapies against specific biological events in malignant cellular clones.
Audio and slides for this presentation are also available on YouTube: http://youtu.be/ukXhuy5cXrE
Huma Q. Rana, MD, a cancer geneticist with Dana-Farber Cancer Institute, explains the cancer risk associated with BRCA1 and BRCA2 gene mutations. This presentation was originally given on July 23, 2013 as part of the "What Every Woman Should Know" event put on by Dana-Farber's Susan F. Smith Center for Women's Cancers.
It describes the prevalence of Breast Cancer among BRCA 1/2 mutations with special consideration to biological background, detection and screening, actions taken upon discovering mutation carriers and whether we have a different therapeutic algorithm than sporadic cases. Special emphasis on the role of PARP inhibitors in the management of metastatic disease.
What are the latest treatment advances for HER2-positive metastatic breast cancer? Eric Winer, MD, director of the Breast Cancer Program in the Susan F. Smith Center for Women's Cancers, discusses some of the latest research and treatment options.
This presentation was originally given as part of the 2015 Metastatic Breast Cancer Forum, held on October 17 at Dana-Farber Cancer Institute in Boston, Mass.
For more information, visit www.susanfsmith.org
Breast Cancer Treatment: Where we are, Where we're going - April 24th, 2018Summit Health
Summit Medical Group MD Anderson Cancer Center Lecture Series. A lecture and panel discussion format about the latest advances in surgery and innovative therapies for breast cancer presented by Summit Medical Group MD Anderson Cancer Center Specialists Dr. Lisa Mills, Dr. David Schreiber and Dr. Winnie Polen.
Please share this webinar with anyone who may be interested!
Watch all our webinars: https://www.youtube.com/playlist?list=PL4dDQscmFYu_ezxuxnAE61hx4JlqAKXpR
Cancer care is increasingly tailored to individual patients, who can undergo genetic or biomarker testing soon after diagnosis, to determine which treatments have the best chance of shrinking or eliminating tumours.
In this webinar, a pathologist and clinical oncologist discuss:
● how they are using these new tests,
● how they communicate results and treatment options to patients and caregivers, and
● how patients can be better informed on the kinds of tests that are in development or in use across Canada
View the video: https://youtu.be/_Wai_uMQKEQ
Follow our social media accounts:
Twitter - https://twitter.com/survivornetca
Facebook - https://www.facebook.com/CanadianSurvivorNet
Pinterest - https://www.pinterest.com/survivornetwork
YouTube - https://www.youtube.com/user/Survivornetca
Strategies for Managing Recurrent Ovarian Cancerbkling
When ovarian cancer returns, it's not uncommon to experience a range of emotions and feel overwhelmed. But it's important to remember that recurrent ovarian cancer can often be successfully treated. Dr. Shannon N. Westin, gynecologic oncologist and clinical investigator at MD Anderson Cancer Center, goes over the latest treatment options for recurrent disease.
El futuro del tratamiento del cáncer renal metastásico: inmunoterapia y terap...Mauricio Lema
Ponencia en el primer simposio de la Asociación Colombiana de Hematología y Oncología (ACHO) de cáncer genitourinario, Bogotá, septiembre 23 y 24 de 2016.
Presentation is highlighting the integration of different modalities in the management of locally advanced and metastatic prostate cancer pointing to the proven values of adding chemotherapy. A special note has been made to oligometastatic disease.
Describes the emerging resistance of epithelial cancer of the ovary to current therapies and the role of PARP inhibitors in the management in view of the recent drug approvals.
Management of MSI High Solid Tumors and the impact of adding Immunotherapy upon improving survival outcome and response rate. Colorectal and Non Colorectal tumors.
Prostate cancer the androgenic fortified dogmaMohamed Abdulla
It describes the androgenic nature of prostate cancer and the androgenic axis should be tackled in all phases of prostate cancer. Also a special emphasis on recent data on management of metastatic hormone sensitive prostate cancer.
Expanding treatment platform in m crc bayer - asyut 2018Mohamed Abdulla
Describes the different therapeutic approach to patients with metastatic colorectal cancer in the 3rd subsequent treatment line with especial emphasis on the role of regorafenib and how to manipulate the adverse events while not compromise the outcome.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
1. Management of TNBC
Mohamed Abdulla M.D.
Prof. of Clinical Oncology - Cairo University
Director of KOSC Advisory Board
Vice President of KASO
KIOW 4th Edition
Corinthia Hotel – Khartoum
Saturday 17/11/2018
2. Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,
Merck Serono, Novartis, Mundipharma, MSD, Ely Lilly, Sanofi-
Genzyme.
• No conflict of interest.
• This presentation does not relate to any product of commercial
interest in particular.
Speaker Disclosures
3. The Simple View:
Three Subtypes of Breast Cancer
ChemotherapyEndocrine therapy Anti-HER2 therapy
HER2, human epidermal growth factor receptor 2; HR, hormone receptor
HR +ve
60 – 70%
HER 2 +ve
15 – 20%
TNBC
15 – 20%
4. Key characteristics of TNBC
• TNBC = ER, PR &
Her2 neu
NEGATIVE
• 10% to 17% of
all breast
carcinomas
• TNBC patients
are generally
younger than
the overall
BC population
• Related to
Hereditary BC
• Significantly
more aggressive
than other
molecular BC
subtypes
• Relapse pattern
• Short disease-free
interval
• Increased incidence
in visceral mets
(74%)
• CNS mets in 46% of
cases
BC
TNBC
TNBC
Boyle P. Ann Oncol. 2012; Anders CK, et al. Clin Breast Cancer. 2009
5. Survival data for different metastatic breast cancer subtypes with triple negative breast cancer (TNBC) faring the
worst (SEER, 2017)
Associated with poor outcomes!
Key characteristics of TNBC
6. Current Treatment Options for Metastatic
TNBC
• Sequential single-agent chemotherapy is the preferred
approach for most pts with metastatic TNBC
– Combination chemotherapy can be used for pts
requiring more rapid response but does not improve OS
Taxanes
Paclitaxel
Nab-paclitaxel
Docetaxel
Anthracyclines
Doxorubicin
Pegylated liposomal
doxorubicin
Epirubicin
Antimetabolites
Capecitabine
Gemcitabine
Other Microtubule
Inhibitors
Vinorelbine
Eribulin
Ixabepilone
Platinum Agents
Carboplatin
Cisplatin
ZeichnerSB, et al. Breast Cancer (Auckl). 2016
• Patients should generally remain on a regimen until best
response, disease progression, or significant toxicity
7.
8. Challenges with TNBC in Daily Practice:
1. Aggressive disease with dismal outcome.
2. Younger age group.
3. Absence of Target to be attacked for decades.
4. Heterogeneous disease (No one size to fit all).
5. The cross talk between TNBC and Hereditary BC.
6. Controversial approach for neoadjuvant, adjuvant and
metastatic sittings.
7. How to apply the identified back-stage molecular players
into therapeutic platform.
10. Neoadjuvant Therapy:
• Direct assessment of in vivo response.
• pCR in TNBC > HR+ HER2- BC (30% vs 7%).
• Highest pCR in Basal-Like 1 (> 50%).
• pCR +ve long term outcome.
• Growing interest in platinum compounds.
von Minckwitz et al. J Clin Oncol 2012;30:1796–804. Masuda et al. Clin Cancer Res 2013;19:5533–40. Liedtke et al. J Clin
Oncol 2008;26:1275–81. Cortazar et al. Lancet 2014;384:164–72.
20. Challenges & Factors Affecting
Treatment Choice:
• Relapse is common with TNBC in 1st 2 years.
• Re-biopsy of metastatic site for discordance.
• Factors Affecting Treatment Choice:
1. Tumor burden.
2. Rate of disease progression.
3. Performance status.
4. Previous treatment received.
5. Patient’s preference.
21.
22. Trying to move away from ONE Size fits all!
TNT: Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ Breast Cancer
Pts with ER-, PgR
unknown, and HER2-
or BRCA1/2+
metastatic or
recurrent LABC
(N = 376)
Carboplatin AUC6 Q3W
x 6 cycles (n = 188)
Docetaxel 100 mg/m2 Q3W
x 6 cycles (n = 188)
For both arms,
crossover upon
progression allowed
Median PFS, Mos Carbo Doc
BRCA1/2 mutated
6.8 4.8
BRCA1/2 not mutated
3.1 4.6
Carboplatin + BRCA1/2 mutated
Carboplatin + BRCA1/2 not mutated
Docetaxel + BRCA1/2 mutated
Docetaxel + BRCA1/2 not mutated
Tutt A, et al. SABCS 2014. Abstract S3-01.
25. DNA Repair –
A Process Essential to Cell Survival
• Each cell sustains 10,000 to 30,000 episodes of DNA
damage per day
• 5 basic types of DNA damage-repair pathways
How long is a piece of DNA?
DNA length per cell 2 meters
Cells per human 2 ˣ 1013
DNA length per human 4 ˣ 1013 meters
Distance from the earth to the sun 1.49 ˣ 1011 meters
Number of return trips to the sun 134
26. BRCA Genes:
Basic Knowledge
Eukaryotic Genome
Constant StressEndogenous Exogenous
Continuous Damage
Continuous Repair
Misrepair Perfect Repair No Repair
Mutations Apoptosis
Tumor Suppressor Genes
Peter J.O’Donovan and David M.Livingston. Carcinogenesis vol.31 no.6 pp.961–967, 2010
BRCA1 & BRCA2
• DNA Repair
• Control of Cell Cycle Checkpoints
• Control of Mitotic Activity
27. BRCA Genes: Basic Knowledge
DNA Repair
NHEJR HR
1 2 1 2
Peter J.O’Donovan and David M.Livingston. Carcinogenesis vol.31 no.6 pp.961–967, 2010
G0, G1,
Early S
Late S,
G2
28. Presented By Elizabeth Swisher at 2015 ASCO Annual Meeting
Risk of Breast Cancer for Women with
BRCA1 & 2 Mutations:
King, Science, New York Breast Cancer Study, 2003
29. Breast Cancer with BRCA Mutations:
Poor Prognosis
1. Early onset of disease more years of lost life.
2. High prevalence of poorly differentiated, high grade and highly
proliferative lesions more common in BRCA1 mutation cases.
3. Higher prevalence of HR –ve and TNBC.
4. Altered sensitivity to systemic agents:
• to platinum and PARP inhibitors.
• to taxanes.
5. Chemotherapy for early small tumors might improve the
outcome.
Rijnsburger et al. JCO 2010;28:5265
Lee et al. Breast Cancer Res Treat 2010;122:11.
Hemel & Domchek. Hematol Oncol Clin North Am 2010; 24:799.
30. Breast Cancer with BRCA Mutation:
Systemic Therapy: PARP Inhibitors:
Wild BRCA 1/2
PARP
REPAIR/APOPTOSIS
SYNTHETIC
LETHALITY
31. Aim and study design
Olaparib vs TPC in BRCA-mutated metastatic breast cancer
Olaparib
300mg*po bid
Treatment of
Physician’s
Choice
FSI May 2014
Status: Ongoing but not recruiting
Patients
• BRCA-mutated MBC
• TNBC or HER2-negative,
ER/PR-positive
• ≤2 prior chemotherapy lines
• Previous treatment must include anthracycline and
taxane
• If patients have received platinum therapy there
should be:
• No evidence of progression during treatment in
the advanced setting
• At least 12 months since (neo)adjuvant treatment
and randomisation
• ECOG PS 0 or 1
• At least one lesion that can be assessed by RECIST
Randomise 2:1
Approximate
N=310
Stratification by
• Prior chemotherapy regimens for
metastatic breast cancer
• Hormonal status
• Prior platinum therapy
Primary endpoint
• PFS (RECIST 1.1,
Independent Review)
Secondary endpoints
• OS
• PFS2
• ORR
• PFS, PFS2 and OS
based on gBRCAm
status
• HRQoL (EORTC-QLQ-
C30)
• Safety and tolerability
Global Study in 19 countries and
approximately 190 sites
ClinicalTrials.gov. NCT02000622.; Robson M, et al. Poster presented at San Antonio Breast Cancer Symposium; 9–13 December, 2014
* tablet formulation (2 tablets twice daily)
32. Olaparib treatment significantly improved PFS assessed by BICR
compared to TPC1
BICR: blind independent centralised review - FAS; Maturity rate: 234/302=77%
Stratified log rank test, stratified by previous chemotherapy for MBC (yes/no) and HR+ versus TNBC. 2 sided p value
1. Robson et al. N Engl J Med. 2017; Epub ahead of print; 2. AZ data on file (2017)
The risk of progression or death over the course of the study was reduced by over 40%1
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Probabilityofprogression-free
survival
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Time from randomisation (months)
Olaparib
Chemotherapy
Number of patient’s at risk
205 201 177 159 154 129 107 100 94 73 69 61 40 36 23 21 21 11 11 11 4 3 3 2 2 1 1 1 0
97 88 83 46 44 29 25 24 21 13 11 11 8 7 4 4 4 1 1 1 1 1 1 1 1 0 0 0 0
Olaparib 300 mg bd (N=205)
TPC (N=97)
Median PFS was improved by 69% with
olaparib treatment compared to standard of
care chemotherapy2
Olaparib TPC
n 205 97
Events (%) 163 (79.5%) 71 (73.2%)
Median (m) 7.0 4.2
HR = 0.58
95 % CI (0.43,0.80)
p=0.0009
PFS free at 6m (%) 54.1 32.9
PFS free at 12m (%) 25.9 15.0
33. Risk of progression was also reduced in olaparib treated patients
with HR+ disease and TNBC compared to TPC1
Patients with HR+
MBC2
Patients with
TNBC2
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Probabilityofprogression-freesurvival
0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Olaparib 300 mg bd (N=103)
Chemotherapy (N=49)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Probabilityofprogression-freesurvival
0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Olaparib 300 mg bd (N=102)
Chemotherapy (N=48)
Olaparib TPC
n 102 48
Events (%) 81 (79.4) 40 (83.3)
Median(m) 5.6 2.9
HR= 0.43
95% CI (0.29, 0.63)
Olaparib TPC
n 103 49
Events (%) 82 (79.6) 31 (63.3)
Median(m) 8.3 5.1
HR= 0.82
95% CI (0.55, 1.26)
1. Robson et al. N Engl J Med. 2017; Epub ahead of print; 2. AZ data on file (2017)
34. PFS results was observed across all pre-specified subgroups
with olaparib treatment compared with TPC1
All patients
Prior chemotherapy for metastatic breast cancer
Yes
No
Receptor status
ER and/or PgR positive
ER and PgR negative
Prior platinum for breast cancer
Yes
No
Measureable versus non-measurable disease
Measureable
Non-measurable
Progressive disease at time of randomization
Yes
No
BRCA mutationtype
BRCA1
BRCA2
Age (years)
<65
≥65
Region
Asia
Europe
North and SouthAmerica
Race
Whit
e
Other
0.58 (0.43 to 0.80)
0.65 (0.47 to 0.91)
0.56 (0.34 to 0.98)
0.82 (0.55 to 1.26)
0.43 (0.29 to 0.63)
0.67 (0.41 to 1.14)
0.60 (0.43 to 0.84)
0.58 (0.43 to 0.80)
0.57 (0.30 to 1.12)
0.60 (0.43 to 0.83)
0.72 (0.41 to 1.30)
0.54 (0.37 to 0.79)
0.68 (0.45 to 1.07)
0.65 (0.49 to 0.88)
Not calculated
0.57 (0.34 to 0.97)
0.71 (0.48 to 1.08)
0.39 (0.22 to 0.73)
0.67 (0.48 to 0.95)
0.51 (0.32 to 0.85)
119 (81.5) : 51(73.9)
44 (74.6) : 20(71.4)
82 (79.6) : 31(63.3)
81 (79.4) : 40(83.3)
50 (83.3) : 21(80.8)
113 (77.9) : 50(70.4)
139 (84.2) : 56(77.8)
24 (60.0) : 15(60.0)
127 (79.9) : 53(72.6)
36 (78.3) : 18(75.0)
94 (82.5) : 41(82.0)
64 (76.2) : 30(66.7)
154 (79.4) : 67(72.0)
9 (81.8) : 4(100.0)
46 (78.0) : 21(75.0)
77 (79.4) : 34(75.6)
40 (81.6) : 16(66.7)
109 (81.3) : 47(74.6)
54 (76.1) : 24(70.6)
Hazard ratio (95%
CI)
Olaparib : TPC, n (%)
163 (79.5) : 71(73.2)
0 0.2 0.4 0.6 0.8 1 1.2 1.4
Olaparib better TPCbetter
NC
1. Robson et al. N Engl J Med. 2017
35. At the final DCO median overall survival in the olaparib arm was 19.3
months compared to 17.1 months in the TPC arm1
• The difference did not reach statistical significance HR = 0.9 (95% CI: 0.66, 1.23) p=0.513
Olaparib 300 mg bd (N=205)
TPC (N=97)
Probabilityofoverallsurvival
1.0
0.0
0.9
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
205
97
199
85
178
74
146
62
124
48
92
40
55
30
23
15
11
5
6
2
0
0
N at risk
Olaparib
TPC
Time from randomization (months)
OlympiAD was not powered to
show an OS benefit1
• At final OS data cut-off;
• 13% of patients in the
olaparib arm and 0% on
the TPC arm remained
on study treatment
• 19% of patients
received olaparib for
more than 18 months
• Median treatment
duration in the olaparib
arm was double that in
the TPC arm at 7.6 and
3.5 months respectively
1. Robson et al. AACR, 2018
36. A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to
physician’s choice of therapy in patients with advanced breast
cancer and a germline BRCA-mutation
Jennifer K. Litton, Hope S. Rugo, Johannes Ettl, Sara Hurvitz,
Anthony Gonçalves, Kyung-Hun Lee, Louis Fehrenbacher, Rinat Yerushalmi, Lida A.
Mina, Miguel Martin, Henri Roché, Young-Hyuck Im, Ruben G. W. Quek, Iulia Cristina
Tudor, Alison L. Hannah, Wolfgang Eiermann, Joanne L. Blum
Litton JK et al. SABCS, 2017
37. Talazoparib (BMN673) Phase III trial : EMBRACA
Primary endpoint
• Progression-free survival by RECIST by
blinded central review
Key secondary efficacy endpoints
• Overall survival (OS)
• ORR by investigator
• Safety
Exploratory endpoints
• Duration of response (DOR) for objective
responders
• Quality of life (QoL; EORTC QLQ-C30,
QLQ-BR23)
Phase 3, international, open-label study randomized
431 patients in 16 countries and 145 sites
Abbreviations: CNS, central nervous system; EORTC, European Organisation for Research and Treatment of Cancer; HER2, human epidermal growth factor receptor 2; mets, metastases; PO, orally (peros);
QLQ-BR23, Quality of Life Questionnaire breast cancer module; QLQ-C30, Quality of Life Questionnaire Core 30; R, randomized; RECIST, Response Evaluation Criteria In Solid Tumors version 1.1;
TNBC, triple-negative breast cancer.
*Additional inclusion criteria included: no more than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease; prior treatment with a taxane and/or anthracycline unless medically
contraindicated.
†HER2-positive disease is excluded. ‡Physician's choice of therapy must be determined prior to randomization.www.clinicaltrials.gov
(NCT01945775)
Patients with locally advanced or metastatic
HER2-negative breast cancer and a germline
BRCA1 or BRCA2 mutation*†
Stratificationfactors:
• Number of prior chemo regimens (0 or ≥ 1)
• TNBC or hormone receptor positive (HR+)
• History of CNS mets or no CNS mets
Talazoparib
1 mg PO daily
Physician's choice of
therapy (PCT)‡:
capecitabine, eribulin,
gemcitabine, or
vinorelbine
R
2:
1
Treatment (21-day cycles)
continues until progressionor
unacceptable toxicity
Litton JK et al. SABCS, 2017
38. Talazoparib (BMN673) Phase III trial : EMBRACA_PFS
• At a median follow-up of 11.2 months, Median progression-free survival (PFS) was 8.6 months (95% CI, 7.2-9.3) with
talazoparib compared with 5.6 months (95% CI, 4.2-6.7) with physician’s choice of therapy (HR, 0.54; 95% CI, 0.41-0.71; P
<.0001).
Litton JK et al. SABCS, 2017
39. Talazoparib (BMN673) PIII EMBRACA_PFS Subgroup
PFS:CNSMetastasesSubgroup
Litton JK et al. SABCS, 2017
Breast cancer brain metastases show increased levels of genomic aberration-based
homologous recombination deficiency scores relative to their corresponding
primary tumors. Ann Oncol. 2018
41. CLINICAL DATA ON THE USE OF
IMMUNE CHECKPOINT INHIBITORS
FOR PATIENTS WITH MTNBC
42. Is breast cancer immunogenic?
High TILs correlate with improved survival in node positive TNBC
TIL effect is linear: the more TILs the better you do: OS: 0.83 (95%CI: 0.71-0.98) p=0.015
Loi et al, JCO 2013; Loi et al Annals of
Oncology 2014
43. KEYNOTE-086: Antitumor Activity of
Pembrolizumab
Cohort A (N = 170): Previously Treated
mTNBC
Cohort B (N = 84): Previously Untreated mTNBC,
PD-L1 Positive
Adams et al 2018
44. IMpassion130 study design
IC, tumour-infiltrating immune cell; TFI, treatment-free interval. a ClinicalTrials.gov: NCT02425891. b
Locally evaluated per ASCO–College of American Pathologists (CAP) guidelines. c Centrally evaluated per
VENTANA SP142 IHC assay (double blinded for PD-L1 status). d Radiological endpoints were investigator
assessed
(per RECIST v1.1). Schmid P, et al. IMpassion130
ESMO 2018 (LBA1_PR) http://bit.ly/2DMhayg
Co-primary endpoints were PFS and OS in the ITT and PD-L1+ populations
Key secondary efficacy endpoints (ORR and DOR) and safety were also evaluated
Key IMpassion130 eligibility criteriaa:
• Metastatic or inoperable locally advanced TNBC
‒ Histologically documentedb
• No prior therapy for advanced TNBC
‒ Prior chemo in the curative setting, including taxanes,
allowed if TFI ≥ 12 mo
• ECOG PS 0-1
Stratification factors:
• Prior taxane use (yes vs no)
• Liver metastases (yes vs no)
• PD-L1 status on IC (positive [≥ 1%] vs negative [< 1%])c
Atezo + nab-P arm:
Atezolizumab 840 mg IV
‒ On days 1 and 15 of 28-day cycle
+ nab-paclitaxel 100 mg/m2 IV
‒ On days 1, 8 and 15 of 28-day cycle
Plac + nab-P arm:
Placebo IV
‒ On days 1 and 15 of 28-day cycle
+ nab-paclitaxel 100 mg/m2 IV
‒ On days 1, 8 and 15 of 28-day cycle
Double blind; no crossover permitted
RECIST v1.1 PD
or toxicity
R
1:1
45. Primary PFS analysis: PD-L1+
population
Data cutoff: 17 April 2018. Schmid P, et al. IMpassion130 ESMO 2018 (LBA1_PR) http://bit.ly/2DMhayg
0 3 6 9 12 15 18 21 24 27 30 33
Months
No. at risk:
Atezo + nab-P 185 146 104 75 38 19 10 6 2 1 NE NE
Plac + nab-P 184 127 62 44 22 11 5 5 1 NE NE NE
7.5 mo
(6.7, 9.2)
5.0 mo
(3.8, 5.6)
100
80
60
40
20
0
Progression-freesurvival
Stratified HR = 0.62
(95% CI: 0.49, 0.78)
P < 0.0001
Atezo+ nab-P
(n = 185)
Plac+nab-P
(n = 184)
PFS events,
n
138 157
1-year PFS
(95% CI),
%
29%
(22, 36)
16%
(11, 22)
46. Interim OS analysis: PD-L1+ population
25.0 mo
(22.6, NE)
15.5 mo
(13.1, 19.4)
100
80
60
40
20
0
Overallsurvival
0 3 6 9 12 15 18 21 24 27 30 33 36
Months
No. at risk:
Atezo + nab-P 185 177 160 142 113 61 36 22 15 9 5 NE NE
Plac + nab-P 184 170 147 129 89 44 27 19 13 6 NE NE NE
Stratified HR = 0.62
(95% CI: 0.45, 0.86)a
Atezo+ nab-P
(n = 185)
Plac+nab-P
(n = 184)
OS events, n 64 88
2-year OS
(95% CI),
%
54%
(42, 65)
37%
(26, 47)
47. TAKE HOME MESSAGE:
• TNBC is a heterogeneous collection of molecularly distinct disease
subtypes with widely differing natural histories
• TNBC is often associated with genomic instability and is
particularly sensitive to platinum salts, especially when associated
with BRCA mutations
• Several promising novel antibody drug conjugates and targeted
therapies are in late-stage development
• PARP inhibitors have clinically important activity in breast cancers
associated with a germline BRCA mutation
• Checkpoint inhibitors have shown activity in TNBC. Patient
selection remains challenging
• Combination approaches are likely to be necessary for activity
in the majority of patients
TNBC, triple-negative breast cancer.
When we are considering which treatment to use for a patient with mTNBC, we must consider what previous treatments the patient has received, whether the patient is a carrier of a deleterious BRCA mutation, whether her disease is symptomatic or causing an impending visceral crisis, and the patient’s lifestyle and preferences. Sequential single‑agent chemotherapy is usually the preferred approach for most patients because doublet therapy is not associated with improved long‑term survival.[11,12] However, there are rare situations—when a patient is very symptomatic as a result of his/her disease—in which doublet therapy may improve the response rate and rapidness of response.
Appropriate first-line agents include taxanes, anthracyclines, antimetabolites, microtubule inhibitors, and platinum agents. In general, we prefer to start on a regimen and continue it until the patient's disease progresses or the patient develops significant toxicity.
To be randomised in the OlympiAD study, patients must have a documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function). Patients whose mutation status is unknown prior to screening must first consent to genetic screening and follow local ethical procedures for such genetic testing. If they meet the other eligibility criteria, their mutation status will be determined prior to confirmation of their eligibility to the study and randomisation. It is estimated that as many as 2800 patients may need to be screened in order to have 310 patients randomised.
Patients can have either triple-negative breast cancer (defined as estrogen receptor [ER]- and progesterone receptor [PgR]- negative [IHC nuclear staining <1%] and HER2-negative [IHC 0, 1+ or 2+ and/or ISH non-amplified with ratio less than 2.0]) or ER/PgR-positive breast cancer, as long as they are HER2-negative. Patients with ER- and/or PgR-positive breast cancer must have received and progressed on at least one line of endocrine therapy either in adjuvant or metastatic setting or are not considered appropriate for endocrine treatment.
Patients must have at least one lesion that can be accurately assessed per RECIST 1.1. This can be measureable or non-measurable.
This is an open-label study due to the different modes of treatment administration, as well as the different toxicity profiles of the control arm. Therefore, the primary endpoint assessment will be by blinded, independent central review of all patient scans.
Additional points to include:
Curves separate early which is reflected in landmark survival analyses.