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Overview of Breast Cancer TRACO Lecture Series - 2009. Farah Zia, MD Medical Officer, DCTD, NCI November 9, 2009. Definition of Breast Cancer Cancer that forms in tissues of the breast: Ducts: Tubes that carry milk to the nipple Lobules: Glands that make milk. Breast Cancer Progression. A.

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overview of breast cancer traco lecture series 2009

Overview of Breast CancerTRACO Lecture Series - 2009

Farah Zia, MD

Medical Officer, DCTD, NCI

November 9, 2009

slide2

Definition of Breast CancerCancer that forms in tissues of the breast:Ducts: Tubes that carry milk to the nippleLobules: Glands that make milk

breast cancer progression
Breast Cancer Progression

A

B

C

D

Time

Normal

In situ

Atypical

Hyperplasia

Local

Invasion

Primary Tumor

Time Points:

Overt non invasive carcinoma

Onset of local invasion

Onset of metastatic dissemination

slide5

Ductal Carcinoma in situ(DCIS) Most common type of non-invasive breast cancer.The cancer is only in the ducts and has not spread through the wall of the ducts into the tissue of the breast.Nearly all women with cancer at this stage can be cured.Best form of early detection is with a mammogram (non-palpable, asymptomatic)

slide6

Lobular Carcinoma in situ(LCIS)This condition begins in the milk glands, but does not go through the walls of the lobules into the breast tissue.Although not a true cancer, it does increase a woman’s risk of developing cancer later in life.It is important that women with LCIS have regular mammograms.

slide7

Invasive Ductal Carcinoma(IDC)This is the most common type of breast ca, accounting for 8 out of 10 invasive breast cancersDuct  breaks thru duct wall  invades tissueFrom there, it may enter the lymphatics and spread to other parts of the body.

slide8

Invasive Lobular Carcinoma(ILC)Lobules  breaks thru wall  breast tissueIt can then enter the lymphatics and spread to other parts of the bodyAccounts for only 1/10 invasive cancers

inflammatory breast cancer ibc
Inflammatory Breast Cancer (IBC)
  • Rare, 1-5% in U.S.
  • Most aggressive form of breast cancer
  • Clinical diagnosis
    • diffuse erythema involving majority breast
    • peau d’ orange
    • erisypeloid edge
    • often no palpable mass
  • Significantly lower overall survival than non-IBC
inflammatory breast cancer
Inflammatory Breast Cancer
  • Dermal lymphatic invasion
  • Stage IIIB (T4d) if not metastatic
  • Compared to non-IBC, more frequently

ER/PR negative

Her2/neu positive

key statistics for breast cancer 2009
Key Statistics For Breast Cancer, 2009
  • Chance of developing invasive breast cancer at some point in a woman’s life: 1 in 8 (12%)
  • In 2009, 192,370 new cases of invasive breast cancer will be diagnosed among women in the US.
  • Also, there will be about 62,280 new cases of carcinoma in situ in 2009.
  • It is the most common cancer diagnosed among American women
  • 2nd leading cause of cancer death, exceeded only by lung cancer.
  • In 2009, about 40,170 women will die from breast cancer in the US
slide15

Relative Survival* (%)By Cancer SiteSite 1974-6 1983-5 1995-9All sites 50 53 64Breast (female) 75 78 88Colon 50 58 63Leukemia 34 41 46Lung and bronchus 13 14 15Melanoma of the skin 80 85 91Non-Hodgkin lymphoma 47 54 59Ovary 37 41 44†Pancreas 3 3 4Prostate 67 75 99

breast cancer risk factors
Breast Cancer Risk Factors
  • Age
  • Prior breast cancer
  • High risk pre-malignant lesion LCIS, ADH
  • Excess endogenous or exogenous hormones
    • Early menarche
    • Late menopause
    • HRT
  • Nulliparity or age >35 at birth of first child
  • History of breast biopsies
  • Family History, e.g. BRCA 1/2
  • Radiation exposure before age 40
  • Mammographic density
  • Energy balance, lifestyle factors (alcohol)
slide17

Breast CancerScreening MammographyReduces mortality by 26% in women aged 50-74,17% in women 40-49ACS recommends20 or older, BSE20-39 breast exam by physician every three years, 40 or older every yearMammography at age 40 and annually thereafter

two major limitations mammography
Two Major Limitations:Mammography
  • Fails to detect 20% of cancer that become palpable within 1 year
  • Sensitivity less in denser (younger) breasts
other modalities of screening in high risk women
Digital Mammography

Overall accuracy=to film mammograms

Better accuracy in

<50 yrs

Increased mammographic density

Pre/peri menopause

MRI

2-6% of cancers seen only on MRI alone

Sensitivity for MRI higher than mammo

Specificity for MRI lower than mammo

More false + , more biopsies

Promising technique, need longer follow up and survival data

Other modalities of screening in high risk women
breast cancer early stage
BREAST CANCER: Early Stage

Metastasis to ipsilateral axillary lymph node(s)

N1 = movable

N2 = fixed to one another or to other structures

M0 = no distant metastasis

breast cancer spread to lymph nodes
BREAST CANCERSpread to lymph nodes

Supraclavicular

Subclavicular

Distal (upper)

axillary

Central (middle)

axillary

Proximal (lower)

axillary

Mediastinal

Internal mammary

Interpectoral

(Rotter’s)

systemic therapy
Systemic Therapy
  • Endocrine Directed (Hormone) Therapy
  • Chemotherapy
  • Biologic agents
    • Trastuzumab (Herceptin)
    • Bevacizumab (Avastin)
slide24

Targeting the Estrogen PathwayBlock receptorSERM (selective estrogen receptor modulators)Tamoxifen treatmentRaloxifene preventionDecrease ligandAromatase inhibitorsOopherectomyGnRH analogs

slide26

Tamoxifen Pharmacogenetics …. A Developing Area…. JAMA, Oct. 7, 2009 The growth inhibitory effect of tamoxifen is mediated by its metabolites:4-hydroxytamoxifenEndoxifenThe formation of these active metabolites is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6) enzyme

slide27

CYP 2DG VariantsApproximately 100 CYP 2D6 genetic variants have been identified.These manifest in the population as 4 distinct phenotypes:Extensive (normal activity)Intermediate (reduced activity)Poor (no activity)Ultra-rapid (high activity)Thus, it can be speculated that genotype related differences in the formation of active metabolites influence therapeutic response to tamoxifen.

slide28

CYP 2DG VARIANTSTo investigate this relationship:Genotyped tumor tissue DNA for CYP2D6 variations in 1,325 breast cancer patients taking adjuvant tamoxifen.Women were classified as having either: 1. Extensive Metabolism (609 pts) 2. Heterozygous extensive/intermediate (637 pts) 3. Poor metabolism (79)Researchers found clear evidence that breast cancer was more likely to return in pts with reduced or absent CYP 2D6 function

slide29

CYP 2DG ACTIVITYExtensive metabolizers have a 14.9% recurrence at 9 yr FU Heterozygotes have a 20.9% recurrence at 9 yr FU Poor metabolizers have a 29% recurrence at 9 yr FU

aromatase inhibitors ai ai s are drugs that reduce the level of estrogen in postmenopausal women
Aromatase Inhibitors (AI):AI’s are drugs that reduce the level of estrogen in postmenopausal women.
slide31
Aromatase Inhibitors:Currently, 3 AI’s are approved by U.S. FDAAnastrozole (Arimidex)Letrozole (Femara)Exemestane (Aromasin)
slide32

Trials of AIs in the early adjuvant setting. In the ATAC trail patients received tamoxifen x5, anastrozole x 5 or tamoxifen + anastrozole x 5 resulting in a 22% improvement in DFS on anastrozole.In the BIG I-98 trial patients received tamoxifen x 5, letrosole x 5, tamoxifen x 2 + letrozole x 3 or tamoxifen x 3 + letroxole x 2.In the IES trial pateients received tamoxifen x 2-3 + tamoxifen x 2-3 or exemestane x 2-3 resulting in a 32% improvement in DFS with exemestane.In the ABCSGi ARNO 95 Ita trial pateints receive tamofen x 2-3 plus tamoxifen x 2-3 or anastozole x 2-3 resulting in a 43% improvement in DFS on letrozole.

slide33
Breast cancerShould aromatase inhibitors be used in place of tamoxifen?Is there a role for sequential therapy with an AI and Tam?
slide34

SABCS 2008: Meta-analysis: Adjuvant Aromatase Inhibitors vs Tamoxifen in Postmenopausal WomenData was pooled from all trials started by 2000, prospectively comparing an AI and tamoxifen.The large number of events properly powered the subgroup analysis.

slide35

In the meta-analysis 9,856 breast cancer patients received: TAM x 5 yrs vs AI x 5 yrs.The 5 year recurrence with TAM or AI was 12.6% and 9.6% respectively. The 8 year recurrence with TAX or SI was 19.2 and 15.3% respectively.

slide36

AI’s reduced breast cancer recurrence.AI’s were associated with an absolute 2.9% lower recurrence rate at 5 years, that improved to a 3.9% gain at 8 years (15.3% vs 19.2%, P < 0.00001).Mortality Analysis, although still early at 3.9 years fu, showed a small, non-significant advantage to 5 years of AI mono-therapy. Gains of 1.1 % and 0.5% for 5 and 8 year breast cancer mortality.

slide37

AI’s reduced breast cancer recurrence.In 9015 patients treated with Tam x 2-3 years then aldosterone x 2-3 years, the 3 years recurrence for Tax or AI was 8.1% and 5% respectively.Patients treated with TAX or AI, the 6 year recurrence was 16.1% and 12.6% respectively.

slide38

Switch to an AI (after 2-3 years on TAM): absolute gain of 3.1% lower recurrence rate at 3 yrs after the switch and 3.5% at 6 years after the switch (P<0.00001) 0.7% lower breast cancer mortality at 3 years and 1.6% at 6 years (P=0.02)

slide39

How Long Should You Take AI’s? Studies are ongoingNo current absolute guidelinesAdjuvant options per the oncologists discretion include:Primary Rx  AI x 5 yrsPrimary Rx  TAM x 2 or 3 yrs  AI x 2 or 3 yrsPrimary Rx  TAM x 5 yrs  AI x 5 yrs * Note: current standard of care = AI, Max 5 years Rx

slide42

EBCTCG: Systemic therapy28,000 women in 56 trials: Meta-analysisImpact of Polychemotherapy On Absolute Risk Reduction at 5 years (in % )Subgroup age < 50, Node- had a Recurrenceof 9.9% (SE 1.3).Subgroup Age < 50, Node+ had a recurrence of 14.6% (SE 2.3).Subgroup Age 50-69, Node- had a recurrence of 5.3 (SE 1.0).Subgroup Age 50-69, Node + had a recurrence of 5.9 (SE 1.0).

adjuvant systemic polychemotherapy
Adjuvant Systemic Polychemotherapy
  • Polychemotherapy is more effective than single agent
  • Proportional benefits not affected by nodes, ER, menopausal status, or use of tamoxifen
  • Compared with CMF, anthracyclines produced an absolute benefit of 4% in recurrence and survival
adjuvant chemotherapy options
Low risk/

lymph node negative

AC x 4

CMF x 6

CAF x 6

FEC-100

Lymph node positive/high risk

Dose dense AC x 4  Paclitaxel x 4 (q2wk)

AC x 4  Docetaxel x 4 (q3wk)

TAC x 6 (q3wk)

Trastuzumab if HER2 positive

Adjuvant Chemotherapy Options
slide46

ErbB2/HER2 Action in Breast CA Member of the membrane-spanning type I receptor tyrosine kinase family, comprising 4 closely related family members.They dimerize upon ligand stimulation and transduce their signals by subsequent autophosphorylation, catalyzed by the receptor tyrosine kinase activity.This results in recruitment of an array of downstream signaling cascades (survival and mitogenic ) The incidence of ErbB2 amplification is ≈ 30% in breast cancer …Identifying it as a therapeutic target

the egfr her family
The EGFR/HER Family

HRG

(NRG1)

HB-EGF

-cel

Epi

EGF

HB-GF

Amp

TGF

NRG1

NRG2

Epi

NRG3

Ligand

binding

domain

NRG4

Transmembrane

Tyrosine

kinase

domain

neu

Erb-b2

HER2

Erb-b3

HER3

Erb-b4

HER4

erb-b1

EGFR

HER1

slide48

HER-2: TrastuzumabBench to BedsideTargets HER2 proteinHigh affinity (Kd = 0.1 nM) and specificity95% human, 5% murineDecreases potential for immunogenicityIncreases potential for recruiting immune effector mechanisms Early-stage breast ca: 2005 - Herceptin + Chemo ↑OS ↑DFS

HER2 epitopes recognized by hypervariable murine antibody fragment

Human IgG-1

slide49

NSABP B-31Control: ACTThe patient receives4 treatments of doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4 followed by 4 treatments of paclitaxel (T) 175 mg/m2 q 3 wk x 4. Alternatively the patient receives 4 treatments of doxorubicin/cyclophosphamide (AC) 60/600 mg/m2 q 3 wk x 4 followed by 4 treatments of paclitaxel (T) 175 mg/m2 q 3 wk x 4followed by 4.5 treatments of trastuzumab (H) 4mg/kg LD + 2 mg/kg/wk x 51

n9831 and b 31 disease free survival
N9831 and B-31:Disease-Free Survival

ACTH

87%

85%

ACT

75%

%

67%

N Events

ACT 1679 261

ACTH 1672 134

HR=0.48, 2P=3x10-12

ASCO 2005

B31/N9831

Years From Randomization

slide52

Triple –negative breast cancer refers to a specific subtype of breast cancer that does not express the genes for:Estrogen Receptor (ER) Progesterone Receptor (PR) HER2/neu

slide53
It is diagnosed more frequently in:Younger women African Americans Hispanics Women with BRCA1 mutations
slide54

Triple-negative breast ca is clinically characterized as:More aggressiveLess responsive to standard chemotherapy treatmentAssociated with a poorer overall prognosis

slide55

Development of New Treatment Strategies For Triple Negative Breast Cancer ASCO, 2009PARP (poly ADP-ribose polymerase) Inhibitors:n experimental class of drugs that may have potential for the treatment of triple-negative breast cancer. PARP is an enzyme used by cancer cells to repair DNA damage.PARP inhibitors are being used to target tumors where one pathway is already shut down. - BRCA1/BRCA2 mutations lose a form of DNA repair and rely more heavily on the PARP pathway - Tumors which are either concurrently or pre-treated with chemotherapy also have damaged DNA repair pathways.

two parp inhibitors currently in phase i ii clinical trials bsi 201 iv olaparib oral
Two PARP Inhibitors Currently in Phase I/II Clinical Trials:BSI – 201 (IV) Olaparib (Oral)
slide57

BSI-201116 women with triple-negative metastatic breast cancer randomized to standard chemotherapy vs standard chemo therapy + BSI-201. Median survival of 5.7 months with standard chemotherapy versus 9.2 months with BSI-201 plus chemotherapy.………………...

slide58

How can we do better?Better selection of chemotherapy regimensGene expression profiling to predict response to particular agents Better selection of patients for treatment with chemotherapyTreat only those patients who are most likely to recur AND who will therefore benefit most from the addition of chemotherapy… TAILORx Trial

predicting response to chemotherapy
Predicting Response to Chemotherapy
  • Neoadjuvant (pre-surgical) chemotherapy allows for assessment of tumor response to treatment
  • Allows us to identify factors associated with response
gene expression profiling to predict chemotherapy response
Gene Expression Profiling to Predict Chemotherapy Response
  • 24 patients treated with neoadjuvant docetaxel therapy
  • Divided into responders and non-responders
  • Identified 92-genes correlated with response to docetaxel
molecular portrait of breast cancers

“Normal”

Luminal B

HER-2

Basal-like

Luminal A

Molecular Portrait of Breast Cancers
slide62

An Important Question in Breast Cancer TreatmentWhat is the likelihood of distant recurrence in patients with breast cancer who have no involved lymph nodes and estrogen-receptor positive tumors? - These patients prognosis is poorly defined by histopathological and clinical measures alone

slide63

Oncotype DX A multi-step approach was used to:Develop an assay for the expression of tumor related genes for use with paraffin-embedded tumor tissue To validate the assay clinically

slide64

RT-PCR method was developed to quantify gene expression with paraffin-embedded tumor tissue.250 candidate genes were selected from published literature, genomic databases, and experiments based on DNA arrays done on fresh-frozen tissue.Data was analyzed from three independent clinical studies of breast ca involving 447 patients to test the relationship between expression of the 250 candidate genes and the recurrence of breast cancer.

slide65

Three Breast Cancer Studies Used To Select 21 Gene Panel 16 Cancer and 5 Reference Genes4. used the results of the 3 studies to select a panel of 16 cancer related genes and 5 reference genes. - Best RT-PCR performance - Most robust predictionsDesigned an algorithm based on the levels of expression of these genes to compute a recurrence score for each tumor sample being tested.Genes for proliferation (Ki-67, STK15, Survivin, Cyclin B1, MUBL2), estrogen (ER, PR, Bcl2, SCUBE2), invation (Stromolysin 3, Cathepsin L2) HER2 (GRB7, HER2), GSTM1, VD68, BAG1 and reference (Beta-actin, GAPDH, RPLPO, GUS, and TFRC) were studied.

slide66

Validation of Onco DX Paraffin-embedded tissue samples from patients previously enrolled in the NSABP B-14 trial were used to validate the ability of the 21 gene RT-PCR assay and RS algorithm to quantify the likelihood of distant recurrence in patients with: Node-negative, ER+, early stage breast cancer who had been previously treated with tamoxifen.

slide67

Kaplan-Meier Estimates of the Rate of Distant Recurrence at 10 years, If the Onco DX risk score is low (<18) the rate of distant recurrance at 10 years is 6.8%. In the Onco DX risk score is high (>31) the rate According to the Recurrence-Score Risk Categories. of distant recurrence at 10 years is 30.5%.

slide68

Oncotype DXValidated prognostic test for patients treated with hormonal therapy. Based on this study, the recurrence score has been validated as quantifying the likelihood of distant recurrence in tamoxifen-treated patients with node-negative, ER+ breast cancer.

slide69

Oncotype Dx: Chemotherapy benefit.Patients with tumors that have high Recurrence Scores have a large absolute benefit of chemotherapy (similar results with CMF and MF)Patients with tumors that have low Recurrence Scores derive minimal, if any, benefit from chemotherapy.RS < 18 RS = 18-30 RS >30

slide70

Ongoing Research: TAILORxLandmark trial - represents the culmination of a major initiative to integrate molecular diagnostic testing into clinical decision making.NCI is using Oncotype DX to identify and assign treatment to more than 10,000 breast cancer patients from 1,500 sites in the US, Canada, and Peru.

slide71

Purpose: to determine whether adjuvant hormonal therapy is as effective as adjuvant hormonal + chemo for women with a midrange RS. Eligibility: ER+ and/or PR+, Node-negative HER2/neu-negative breast cancerPrimary Objectives: 1. Determine whether adjuvant hormonal tx is not inferior to chemo-hormonal tx in women with a mid-range OncoDX RS (11-25) 2. Create a tissue and specimen bank for patients enrolled in this trial. To include: tumor specimens, tissue microarrays, plasma, & DNA from peripheral blood.

slide72

Schema: TAILORxStage I or II, ER+ and/or PR+, node-negative, HER2/neu negative, tumor size 1.1 – 5.0 cm Oncotype DX AssayRegister specimen bankingRS < 10 Hormone therapy registry RS 11 – 25, RandomizeHormone Rx vs. Chemotherapy + Hormone Rx RS > 25 Chemotherapy +Hormone Rx

17

tailorx key points
TAILORx: Key points
  • TAILORx will examine whether genes that are frequently associated with recurrence for women with early stage breast cancer can be used to assign patients to the most appropriate and effective treatment.
  • The results of this trial could eventually spare many women the unnecessary toxicity of chemotherapy. (currently, ≈ 10% considered low risk; with RS score, 50%).
  • It is one of the first trials to examine a methodology to personalize cancer treatment!
slide75

Characteristics of MBCMedian survival approximately 2 to 3 years, with a 5-year survival of about 20%About 10% of women present at diagnosis with newly diagnosed metastatic breast cancer (MBC).Metastatic disease is considered incurable

slide76
Goals of Treatment of MBCProlongation of survivalImprovement of quality of life - Improvement of symptoms - Acceptable toxicity
systemic treatment approach for metastatic breast cancer
Systemic Treatment Approach for Metastatic Breast Cancer

Metastatic Breast Cancer

  • Limited metastases (bone & soft tissue)
  • Positive hormone receptors
  • Hormone responsive
  • Disease-free interval 2 years
  • Extensive metastases or visceral crisis
  • Negative hormone receptors
  • No response to hormones

Hormonal Therapy

Chemotherapy

Response

No response

No progression

Progression of disease

If disease progresses, second-line hormonal therapy

Second-line chemotherapy

slide78

Metastatic Breast Cancer: Hormonal therapySelective Estrogen Receptor ModulatorsTamoxifen, toremifene Aromatase Inhibitors (post-menopausal)Anastrozole, letrozole, or exemestane Selective Estrogen Receptor DownregulatorsFulvestrantProgestinsmegace 40 mg po 4 x dailyOvarian suppression (pre-menopausal) luteinizing hormone releasing analogoophorectomy

slide79

Hormone positive post-menopausal Metastatic Breast CancerFirst line: Antiestrogen or Nonsteroidal AI Anastrozole or Letrozole.Second line: Nonsteroidal AI or Antiestrogen.Third line: Steroidal AI:exemestane. Fourth line: Progestin. Fifth line: Androgen. If no response use chemotherapy

slide80

First - Line ChemotherapyAgent ORR (%)Docetaxel (75-100 mg/m2) 48-68ixabepilone 42Nab paclitaxel 33Paclitaxel (175-250 mg/m2) 29-63Doxorubicin (60-75 mg/m2) 43-54Capecitabine 35-50Vinorelbine 30-41Gemcitabine 25-37Carboplatin 7-35Cisplatin 9-50Cyclophosphamide 36Flourouracil 28Methotrexate 26

for her 2 positive patients add trastuzumab herceptin bevacizumab avastin
For HER-2 positive patients add Trastuzumab (Herceptin)Bevacizumab (Avastin)
slide82

Bevacizumab (Avastin®):Humanized monoclonal antibody directed against all isoforms of VEGF-A (potent vasodilator and inducer of pathologic angiogenesis). - binds to VEGF, inhibits VEGF receptor bindingLaboratory and clinical evidence supports the central role of angiogenesis in the progression of breast cancer.Multiple angiogenic factors are expressed by invasive breast cancers - 121-amino-acid isoform of VEGF predominates

slide83

Bevacizumab in the First –line Treatment of Locally Recurrent or MBC ECOG 2100 TrialStratify: DFI < 24 mos. vs. > 24 mos. < 3 vs. > 3 metastatic sites Adjuvant chemotherapy yes vs. no ER+ vs. ER- vs. ER unknownRandomize and treat with paclitaxel + Bevacizumab or paclitaxel alone

ecog 2100 response

P<0.0001

P<0.0001

ECOG 2100: Response

34.3%

28.2%

16.4%

14.2%

316

330

250

236

bevacizumab future directions
Bevacizumab: Future Directions
  • Addition of bevacizumab to paclitaxel
    • Significantly prolongs progression free survival, but not overall survival
    • Increases objective response rate
  • Further studies are:
    • Exploring the role of Bevacizumab in the adjuvant setting (BEATRICE Trial: Phase III/Triple-negative breast)
    • Developing methods to identify patients who are most likely to benefit from VEGF-targeted therapies
overview molecular targets
Overview: Molecular Targets

Immune System Activation (Vaccines, Monoclonal antibodies)

Antireceptor Antibodies ± Toxins

Metalloproteinase Inhibitors

Tumor Cell

Antimetabolites

Microtubule inhibitors

Growth Factor Receptors

Matrix Degradation

(Collagenases,

Gelatinases &

Stromelysins)

Tyrosine Kinase Inhibitors

Nucleus

Farnesyl Transferase Inhibitors

Intracellular Signaling Molecules

Angiogenesis Inhibitors (Angiostatin, Endostatin& Anti-VEGF)

Apoptosis Agonists

Hormone Agonists/ Antagonists

Antisense

challenges for the future
Challenges for the future
  • Identify women more specific risk profiles and tailor preventive interventions
  • Identify subsets of patients for whom systemic therapy can be avoided
  • Tailor systemic therapy to individual tumor/host characteristics
    • Targeted therapy: ER, HER2, EGF-R, PARP Inhib
    • Novel targets and pathways