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
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.
Optimizing Therapeutic Strategies in Castration-Resistant Prostate Canceri3 Health
This activity will discuss emerging efficacy and safety data on novel therapies for nmCRPC and mCRPC, strategies to manage adverse events, and the role of imaging studies and PSA testing in evaluating treatment response.
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
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.
Optimizing Therapeutic Strategies in Castration-Resistant Prostate Canceri3 Health
This activity will discuss emerging efficacy and safety data on novel therapies for nmCRPC and mCRPC, strategies to manage adverse events, and the role of imaging studies and PSA testing in evaluating treatment response.
NSCLC: diagnóstico molecular, pronóstico y seguimiento; CTCMauricio Lema
Lo nuevo en diagnóstico molecular, pronóstico y seguimiento en NSCLC, y el impacto pronóstico de las Células Tumorales Circulantes. Para evento de cirugía de tórax, Hotel Intercontinental, Medellín, 22.05.2018 (se complementa con las la presentación de lo nuevo en terapia sistémica en NSCLC).
Proteogenomic analysis of human colon cancer reveals new therapeutic opportun...Gul Muneer
We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development.
FACTORS AFFECTING INITIAL CYCLOSPORINE A LEVEL AND ITS CORRELATION WITH CLINI...Alok Gupta
FACTORS AFFECTING INITIAL CYCLOSPORINE A LEVEL AND ITS CORRELATION WITH CLINICAL OUTCOME INACUTE LEUKEMIA PATIENTS UNDERGOING ALLOGENEIC STEM CELL TRANSPLANTATION
Hepatitis B infection in Stem cell transplant patients and role of lamivudine...Alok Gupta
The presentation describes Hepatitis B infection in Stem cell transplant patients and role of lamivudine prophylaxis in prevention.
The presentation was made at annual meeting of Mumbai Hematology Group held at ACTREC, Mumbai in 2014.
The presentation describes various facts about breast and cervical cancer including burden of disease, survival outcomes, need for early diagnosis and screening recommendations.
Cancer screening - Evidence, Expected benefits, Methods and Current Recommend...Alok Gupta
The presentation discusses about Cancer screening - Evidence, Expected benefits, Methods and Current Recommendations.
The was presented in HEALTH CONNECT meeting at Max Hospital, Saket, new Delhi in 2016.
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
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
The Gram stain is a fundamental technique in microbiology used to classify bacteria based on their cell wall structure. It provides a quick and simple method to distinguish between Gram-positive and Gram-negative bacteria, which have different susceptibilities to antibiotics
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
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
CDSCO and Phamacovigilance {Regulatory body in India}NEHA GUPTA
The Central Drugs Standard Control Organization (CDSCO) is India's national regulatory body for pharmaceuticals and medical devices. Operating under the Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India, the CDSCO is responsible for approving new drugs, conducting clinical trials, setting standards for drugs, controlling the quality of imported drugs, and coordinating the activities of State Drug Control Organizations by providing expert advice.
Pharmacovigilance, on the other hand, is the science and activities related to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems. The primary aim of pharmacovigilance is to ensure the safety and efficacy of medicines, thereby protecting public health.
In India, pharmacovigilance activities are monitored by the Pharmacovigilance Programme of India (PvPI), which works closely with CDSCO to collect, analyze, and act upon data regarding adverse drug reactions (ADRs). Together, they play a critical role in ensuring that the benefits of drugs outweigh their risks, maintaining high standards of patient safety, and promoting the rational use of medicines.
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.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
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1. Molecular Mechanisms of CRPC
Dr Alok Gupta
MD, DM,
Consultant Medical Oncologist
Max Super Speciality Hospital, New Delhi
Ex-Asst. Professor, AIIMS, New Delhi
2. Outline
DNA Damage Response Pathways
Genomic alterations in mCRPC
Therapeutic implications of Genomic alterations in mCRPC
HRD - PARP inhibitors and synthetic lethality
MMR defects and immune checkpoint inhibitors
3. DNA Damage Response (DDR)
Cellular DNA is subject to continuous damage from both environmental
agents (mutagens) and endogenous sources
‒ 1000s of events/day (eg, ssDNA and dsDNA breaks, alkylation, x-linked)
DDR has evolved to maintain DNA sequence and fidelity
Inherited defects in DDR are among the most carcinogenic of all
hereditary syndromes (eg, Lynch syndrome, HBOC)
Some DDR defects can be exploited for therapeutic benefit
O’Connor MJ. Mol Cell. 2015;60:547-560.
4. DNA repair gene mutations
• Evolution of next-generation sequencing has allowed germline DNA repair gene mutations
to be linked to PCa
Single strand DNA repair
pathways
Double strand DNA repair pathways
Mismatch repair (MMR) Homologous recombination (HR)
Base excision repair Non-homologous end joining (NHEJ)
Nucleotide excision repair
DNA damage response (DDR)
5. EZH2
AR gene expression
Mutation/gain/V7
PCA3
AMACR
Prostatic
intraepithelial
neoplasia
Localized
PCa
Loss of 8p
(NKX3.1)?
Activation of
β-catenin, wnt
Loss of APC
Castration-
resistant
PCa
Metastatic
PCa
Curable
Incurable
Normal
prostatic
epithelium
Epigenomic changes,
including GSTP1
hypermethylation
Inactivation of p53, RB1, CDK12
ETS gene family
activation via fusion
with TMPRSS2 or other
AR-driven genes
cMYC
Mutations in SPOP, FOXA1, epigenetic regulators
Anaplastic/
NE PCa
Loss of PTEN, 13q (RB1), 5q (CHD1),
16q, 6q, 3p (FOXP1, SHQ1)
Gain of 8q, 3q (PIK3CA)
Tx
Genomic Alterations in Prostate Cancer Progression
Slide credit: clinicaloptions.com
Compromised DNA repair
6. Germline vs Somatic Mutations
Griffiths AJ, et al. An Introduction to Genetic Analysis. 7th edition. 2000.
Half of gametes
carry mutation
Embryo
All cells in
offspring carry
1 mutated
alleleSperm
Germline
mutation
Germline Mutation
HERITABLE
Somatic Mutation (Tumor Specific)
NONHERITABLE
Mutation only
in cells of
affected area
Embryo
None of
gametes carries
mutation
Somatic mutation
Sperm
Slide credit: clinicaloptions.com
7. 11.8% (82/692) of men with metastatic
prostate cancer inherited a germline
DNA repair mutation vs 4.6% of
499 men with localized disease
Germline Mutations in Prostate Cancer: 1 in 10
Pritchard CC, et al. N Engl J Med. 2016;375:443-453.
Distribution of Presumed Pathogenic
Germline Mutations
PALB2 4%
RAD51D 4%
ATR 2%
NBN 2%
PMS2 2%
GEN1 2%
MSH2 1%
MSH6 1%
RAD51C 1%
MRE11A 1%
BRIP1 1%
FAM175A 1%
BRCA2 44%
ATM 13%
CHEK2 12%
BRCA1 7%
Gene No. of Mutations % of Men
BRCA2 37 5.35
ATM 11 1.59
CHEK2* 10 1.87
BRCA1 6 0.87
Presumed Pathogenic Germline Mutations
in Metastatic Cases (N = 692)
*n = 534; data censored for metastatic cases with inadequate sequencing.
8. More aggressive PCa (vs. non-carriers)
• BRCA2
• Younger onset, higher T stage, higher Gleason, more LN involvement,
shorter PCa-specific survival and OS1,2
• BRCA2 or BRCA1 or ATM :
• 4-fold higher risk lethal PCa, shorter OS3
• BRCA1 :
• Higher recurrence rates, shorter PCa-specific survival4
1J Natl Cancer Inst. 2007;99(12):929
2J Clin Oncol. 2013;31(14):1748
3Eur Urol. 2017;71(5):740
4Clin Cancer Res. 2010;16(7):2115
Germline DNA repair gene mutations & Prostate Cancer
9. DNA Repair Defects in Localized Prostate
Cancer
Sequence analysis of localized, nonindolent prostate tumors with
similar risk profiles (N = 477)
– 200 whole-genome sequences, 277 whole-exome sequences
47/477 (9.9%) tumors had DNA repair mutations
– FANCA (n = 9)
– ATM (n = 8)
– RAD51 (n = 7)
– CDK12 (n = 6)
– BRCA2 (n = 5)
Fraser M, et al. Nature. 2017;541:359-364.
10. Genomic Landscape of Advanced Prostate Cancer
23% of metastatic
CRPCs harbor DNA
repair alterations
The frequency of
DNA repair
alterations
increases with
disease
progression
Robinson D et al, Cell, 2015
Robinson D, et al. Cell. 2015;161:1215-1228.
11. DNA Repair Defects in mCRPC: Enrichment Analysis in
Primary vs Metastatic Tumors
Tumor Samples (N = 918)
Primary
Metastasis
583
335
CARD11
Primary
DNA repair defects: 11%
Metastases
DNA repair defects: 21%
Significance
(Fisher’s qvalue)
Genomic Alteration Frequency
AlteredPrimarySamples(%)
Altered Metastatic Samples (%)
50
10
5
30
0
0 5 10 30 50
Amplification/mutation
Homdel/mutation
Mutation
SPOP
PTEN
KMT2C
KMT2D
MYC
FOXA1
TP53
RB1
BRCA2
AR
ZFHX3
CDK12 APC
IDH1
RYBP/FOXP1
JAK1
SPEN
IGF2R
PREX2
CTNNB1
CCND1
FAT1
MGA
MED12
USP28
ANKRD11
GNAS
ERF
CHD8
GRIN2A
RNF43
USP7 ASXL1
SAMD9
Armenia J, et al. ASCO 2017. Abstract 131.
13. PARP Biology
PARP (polyADPribose polymerase) enzymes play a key role in the repair of
ssDNA breaks via BER pathway
Bind directly to sites of DNA damage
Once activated, uses NAD as a substrate to add large, branched chains of
poly(ADP-ribose) polymers (ie, PARylation) to itself and interaction partners
Recruits other DNA repair enzymes to site of damage
DNA damage
NAD+ Nicotinamide
+ pADPr
Lig3XRCC1
Polß
PNK
PARP
Ohmoto A, et al. Onco Targets Ther. 2017;10:5195-5208.
14. Synthetic Lethality Hypothesis
Farmer H, et al. Nature. 2005;434:917-921. Bryant et al. Nature. 2005;434:913-917.
Repair,
Survival
Repair,
Survival
Normal cell
Non-BRCA mutation carrier
PARP function
BRCA function
PARP inhibitor
PARP function
BRCA function
DNA damage
Repair,
Survival
Repair,
Survival
Normal cell
BRCA mutation carrier
(1 allele lost)
PARP function
BRCA function
PARP inhibitor
PARP function
BRCA function
DNA damage
Repair,
Survival
Cell Death
Cancer cell
BRCA mutation carrier
(both alleles lost)
PARP function
BRCA function
PARP inhibitor
DNA damage
PARP function
BRCA function
15. TOPARP: Trial of Olaparib in mCRPC
30 patients 20 patientsTotal: 50 patients
(49 evaluable)
Eligibility: Histologically confirmed metastatic CRPC, ECOG 0-2, no previous PARPi or platinum
Mateo J, et al. N Engl J Med. 2015;373:1697-1708.
FIRST PART:
TREATED
UNSELECTED
mCRPC pts
Randomized study
in unselected
mCRPC pts
Biomarker guided
patient selection in
next part (Part B)
END OF TRIAL
High response rate:
≥ 50% Responding
Intermediate RR
(10-50% responding)
Putative biomarker
identified (RR > 50%)
Low antitumor
activity RR < 10%
17. Radiologic PFS by Presence of Genomic
Defects in DNA Repair Genes
OS by Presence of Genomic Defects in
DNA Repair Genes
ProportionofPatients
ProportionofPatients
Mateo J, et al. N Engl J Med. 2015;373:1697-1708.
0
0.25
0.50
0.75
1.00
0 1 2 3 4 5 6 7 8 9 101112 131415 16171819 20
Mos Since Trial Entry
Log-rank P < .001
Biomarker positive,
median: 9.8 mos
Biomarker negative,
median: 2.7 mos
0
0.25
0.50
0.75
1.00
0 1 2 3 4 5 6 7 8 9 101112 131415 16171819 20
Mos Since Trial Entry
Log-rank P = .05
Biomarker positive,
median: 13.8 mos
Biomarker negative,
median: 7.5 mos
TOPARP-A: PFS and OS by Presence of DNA Repair
Defects
All patients (N = 50) treated with olaparib 400 mg PO BID
18. De Felice F, et al. Drug Des Devel Ther. 2017;11:547-552.
Olaparib: Ongoing Studies in Prostate Cancer
Trial Study Design Eligibility Study Arms Endpoint Results
TOPARP Phase II Advanced CRPC Oral olaparib ORR 33% ORR
Kaufman, et al Phase II
BRCA1/2-mut adv solid
tumors (PC n = 8)
Oral olaparib ORR
PFS: 9.8 vs 2.7 mos
OS: 13.8 vs 7.5 mos
ORR in PC: 50%
NCT01972217
Randomized
phase II
mCRPC Olaparib + abiraterone Safety
PFS: 7.2 mo
OS: 18.4 mo
(ongoing study)
NCT02484404 Phase I/II
Adv/recurrent solid
tumors
Anti-PD-L1 + olaparib Safety
Recommended
dose (ongoing)
KEYNOTE 365 Phase I/II mCRPC
Anti-PD-L1 + cediranib
± olaparib
Pembro + olaparib
Safety
AEs, ORR, OS
(ongoing)
NCT02893917
Randomized
Phase II
mCRPC Olaparib + cediranib PFS
PFS, RR, OS
(ongoing)
NCT02324998 Phase I Int/high-risk PC Olaparib ± placebo
Degree of
PARPi
AEs (ongoing)
22. KEYNOTE-016: Responses to Pembrolizumab in
MMR-Deficient Tumors
Radiographic responses across 12 tumor types at 20 wks (N = 86)
Le DT, et al. Science. 2017;357:409-413.
Ampulla of Vater
Cholangiocarcinoma
Colorectal
Endometrial cancer
Gastroesophageal
Neuroendocrine
Osteosarcoma
Pancreas
Prostate
Small Intestine
Thyroid
Unknown primary
100
50
0
-50
-100
ChangeFrom
BaselineSLD(%)
Prostate
Prostate
(n = 1)
23. Pembrolizumab for MSI-H or MMR-Deficient
Cancers
In May 2017, the PD-1 inhibitor pembrolizumab received
accelerated approval from FDA for:
– MSI-H or MMR-deficient CRC that has progressed following
treatment with a fluoropyrimidine, oxaliplatin, and irinotecan
– For ALL unresectable or metastatic MSI-H or MMR-deficient
SOLID TUMORS (pediatric and adult) that have progressed on
prior treatment and with no satisfactory alternative treatment
options
Dosage and administration (MSI-H cancers): 200 mg IV every 3
wks
Pembrolizumab [package insert]. 2017.
24. Conclusions
DNA repair mutations are common in prostate cancer, particularly mCRPC
‒ Both somatic and germline mutations can lead to DNA repair defects
20% to 30% of metastatic CRPCs harbor alterations in DNA repair genes
HR DNA repair mutations sensitize to PARP inhibitors
‒ “Synthetic lethality” hypothesis in action
MMR mutations are rare...but may sensitize to immune checkpoint
inhibitors