Affinitor in bc

"Targeted" Therapy for Advanced
Breast Cancer
"Afﬁnitor"
Aumkhae Sookprase!, MD

ศูนย์มะเร็งอุดรธานี
22 พย 2556

Friday, November 22, 2013

(Locally advanced
stage breast cancer)

(Early stage breast
cancer)

(Metastatic stage)

IN THE PAST

• Prognosis

in early stage depend on staging (how
far cancer spread in your body)


TODAY'S UNDERSTANDING

• Prognosis

in any stage depend on biology !
(nature or how aggressive cancer behave)


TISSUE MICROARRAYS IN BREAST
CANCER


PROGNOSIS VARY BY MOLECULAR
SUBTYPES
Luminal A has best prognosis

Basal & HER2 subtypes has worst
prognosis


THE "MUST" HAVE IHC IN
EVERY BREAST CANCER
HER 2
Ki-67
HER2 positive =
3+

E

ER positive = at least
1% staining


ER and PR and HER2 negative
Triple negative
(TN)

Luminal A / B

ER and/or PR positive
and HER2 negative

HER 2

HER 2 +, ER / PR -

ER and PR and HER2 negative

Chemotherapy
Triple negative tumor


Anti-HER 2
HER2 positive tumor

HER 2 +, ER / PR -


HER 2 positive
breast cancer

Normal cell


Anti-hormonal
ER positive tumor

ER and/or PR positive
and HER2 negative

Growth of cancer cells

(ER and PR and HER2 negative)
Basal subtype
Surgery

Chemotherapy
4 - 6 cycles every 3 weeks

Radiation

( size > 5 cms, lymph node involvement)


(ER negative and HER2 negative)
HER 2 subtype
Surgery

Anti- HER 2
(Trastuzumab )
1 yr

+

Chemotherapy

Radiation

( size > 5 cms, lymph node
involvement)

(ER positive and HER2 negative)
Luminal subtype
Surgery

Anti-hormonal
5 yrs

Radiation

+/-

( size > 5 cms, lymph node
involvement)

Chemotherapy

Methods to inhibit ER in Early Stage
TAMOXIFEN

1. NS-AIs : LET, ANA
2.

Nucleus

S-AI : EXE
Post-menopausal


Growth &
proliferation

2. Type of distant metastasis
1.Bone metastasis
2.Soft tissue metastasis
(LN, subcutaneous)
3. Non life-threatening
visceral


1. Life-threatening
visceral : pulmonary,
liver
2. Multiple sites of
metastasis

(survival)

QoL

Factors
1. Patient's factor : Performance status
2. Tumor's factor : Biology (tumor subtype)
3. Treatment's goal

- Rapid response in patient with widespread metastasis
- Toxicity proﬁles in each treatment


Capecitabine
Eribulin

Taxanes

Gemcitabine

FAC

Vinorelbine

Chemotherapy


Ixabepilone

Trastuzumab

Anti-HER 2


Lapatinib

58% ER positive tumors 1

HR+
58%

Anti-hormonal is a
mainstay treatment
1Lertsanguansinchai


P, et al. J Med Assoc Thai. 2002

Anti-hormonal
Tamoxifen
Fulvestrant
Non-steroidal AIs : Letrozole, Anastrozole
steroidal AI : Exemestane
Megestrol acetate
Estrogen

Anti-hormonal

Chemotherapy


Anti-HER 2

Methods to inhibit ER
TAMOXIFEN
Pre-menopausal

FULVESTRANT

OFS
(GnRH or
surgical)

1. NS-AIs : LET, ANA
2.

Nucleus

S-AI : EXE
Post-menopausal


Growth &
proliferation

HR + MBC
Life-treatening HR+ MBC

Non - life-treatening HR+ MBC

1st line CT Response
PD
PD
2 nd line CT
PD
3 rd line CT
PD
4 th line CT
PD

Response

2 nd line
PD Maintenance HT

Response 3 rd line
Maintenance HT
PD
Response

Later line of CT


1 st line
Maintenance HT

4 th line
Maintenance HT

HR + MBC
Life-threatening HR+ MBC

Non - life-threatening HR+ MBC

PD with life - threatening
metastasis

1st line CT
Not response

1 st line HT

Response

2 nd line HT

2 nd line CT
3 rd line HT
3 rd line CT
4 th line CT
Later line of CT


4 th line HT

Later line HT

Early Stage


Metastatic setting

Timeline of Approval for HR+ Advanced Breast Cancer:
No New Regimens Approved in the Prior Decade

Exemestane
(1999)
Tamoxifen
(1977)
Letrozole
(1997)
Fulvestrant
(2002)

Anastrozole
(1995)

1970 1975 1980 1985 1990 1995 2000 2005 2010 2015

Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.


Schema of treatment options for HR+, postmenopausal
women following different adjuvant therapies


Guideline for ER+/HER2- ABC
• For post-menopausal women, the preferred 1st
line ET is an AI; however, TAM remains a viable
option in selected pts. Type and duration of
adjuvant ET must be taken into account : 1A

Cardozo F, Costa A, Norton L, et al. The Breast 2012.

Must know deﬁnitions in aBC on ET
• Primary (de novo) VS Secondary resistance
1. Primary (de novo)
- Initial resistance (not response to therapy at all)
2. Secondary (acquired resistance)
- Initial response then resistance


Guideline for ER+/HER2- ABC

• Optimal post-AI treatment is uncertain.
Available options include, but are not limited
to, TAM, another AI, fulvestrant and
megestrol acetate : 1A

Cardozo F, Costa A, Norton L, et al. The Breast 2012.

Sequential beneﬁt in ET treatment after 1 NS-AI
"Partial non-cross resistant between AIs"
Initial

Second

N

ORR (%)

CBR(%)

A or L

E

23

8.7

43.5

TTP
(months)
5.1

E

A or L

18

22.2

55.6

9.3

A

E

12

-

-

4.4

E

A

11

-

-

1.9

A

E

50

8

44

5

A or L

E

114

5

46

4

A or L

E

31

19.4

54.8

3.2

A or L

E

30

0

46.6

4

A or L

E

60

20

38.3

3.2

A or L

E

105

4.8

20

3.2

5 - 20

50

3-5

Mostly A or
L

E

Modest Benefit of Single-Agent
Chemotherapy for Advanced BC
Typical Clinical Outcomes
Treatment Line

Response Rate, %

Median TTP, mo

First-line

25 – 45

5–8

Second-line

15 – 30

2–5

Third-line

0 – 20

1–4

Subsequent lines

Limited or no data

Abbreviations: mo, months; TTP, time to progression.
Burstein HJ. ASCO 2010. Metastatic Breast Cancer Oral Abstract
Session.


Mechanisms of Endocrine Resistant
and Potential Molecular Target


HR+ Advanced Breast Cancer

E

Osborne CK, et al. Annu Rev Med. 2011;62:233-247; Yamnik RL, et al. J Biol Chem. 2009;284:6361-6369.

Mechanisms of AI resistance



A. Ineffective
inhibition of AIs



B. Alternative
sources of E



D. Ligandindependent
activation of Esignaling pathways

HER2, FGFR,
EGFR, IGF-1R

HR+ Advanced Breast Cancer

ER
CoA

ER
P

Src

PI3K Ras
AKT MAPK

E
S6KI

mTOR

ER P
P

P
ER P
CoA

P P
ERCoA

P
P
CoA

Osborne CK, et al. Annu Rev Med. 2011;62:233-247; Yamnik RL, et al. J Biol Chem. 2009;284:6361-6369.

Crosstalk Between ER and PI3K/AKT/mTOR
Signaling: Rationale for Dual Inhibition
•mTORC1 activates ER in a
ligand-independent fashion1
•Estradiol suppresses the
apoptosis induced by PI3K/
AKT/mTOR blockade2
•Hyperactivation of the PI3K/
AKT/mTOR pathway is
observed in endocrineresistant breast cancer cells3
•mTOR is a rational target to
enhance the efficacy of
endocrine therapy

Adapted from Johnson SR. Clin Breast Cancer. 2009;9(suppl 1):S28S36.


Potential Therapeutic Target
to Overcome Resistance of
NS-AIs


NEJM, Feb, 2012.


DFS


Timeline of Approval for HR+ Advanced Breast Cancer:
No New Regimens Approved in the Prior Decade

Exemestane
(1999)
Tamoxifen
(1977)

Everolimus +
exemestane
(2012)

Letrozole
(1997)
Fulvestrant
(2002)

Anastrozole
(1995)

1970 1975 1980 1985 1990 1995 2000 2005 2010 2015

Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.


BOLERO-2 : Most Common Adverse Events


Clinically Notables AEs Associated with mTOR
inhibition

Stomatitis
Non-infectious pneumonitis
Infectious
Hyperglycemia, hyperlipidemia
Skin rash


Time to Deﬁnitive Deterioration of QoL
: clinical signiﬁcant


Stomatitis : Clinical manifestation
( all grade 59%, grade 3 : 8%)

Aphthous like ulcers,
discrete, well-demarcated
with whitish
pseudomembrane
Typically develop acutely
in the ﬁrst cycle
Severity peak within 2
weeks of treatment


Rash : Clinical manifestation

Acne inform dermatitis
Start with inﬂammatory
lesion, papule, macule
Distribute over and unusual areas : upper
extremities, trunk, neck


Non-infectious pneumonitis : Radiographic
Obtain base line CXR
"diffuse ground glass or patchy inﬁltration"


Management of Common Adverse Events:
Noninfectious Pneumonitis
Noninfectious pneumonitis may occur with everolimus and
other mTORs1
• Asymptomatic (grade 1 = radiological lung changes only)
• Symptomatic (grade 2 = not interfering with daily activities;
grade 3 = interfering with daily activities; grade 4 = oxygen
indicated)
Diagnosis of noninfectious pneumonitis
• Recommend consultation with pulmonologist
• Follow dose-modification guidelines according to grade of
pneumonitis
• CT scan with lung windows and PFT as indicated; bronchoscopy
with biopsy and/or bronchoalveolar lavage for grade 3 and 4
recommended
1. Atkins et al. J Clin Oncol. 2004;22:909-918.


Everolimus Dose Level Modification
Guidelines: Noninfectious Pneumonitis
Worst
Gradea

Grade 1

Grade 2

Investigation

Management

CT scans with lung windows
Repeat at least every 12 weeks
No specific therapy
until return to within normal limits

CT scans with lung windows
Repeat at least every 12 weeks
until return to within normal limits
Consider PFTb
Consider bronchoscopy with biopsy
and/or BAL

Symptomatic only
Corticosteroids if
symptoms are
troublesome

Everolimus Dose

100%

Reduce everolimus 1 dose level until
recovery to ≤ grade 1
Everolimus may also be interrupted
if symptoms are troublesome
If not ≤ grade 1 within 3 weeks
withdraw patients from study
Everolimus dose cannot be escalated

Grade 3

As for grade 2 with PFT
Repeat at least every 6 weeks until
return to within normal limits
Corticosteroids if of
Bronchoscopy with biopsy and/or
noninfectious origin
BAL recommended
Taper as indicated
Exclude infection/progression of
underlying malignancy

Hold everolimus until recovery to
≤ grade 1
If of clinical benefit, may restart
everolimus within 3 weeks at next
lowest dose level

Grade 4

As for grade 3

Discontinue everolimus


As for grade 3

Reverse or delay resistance
mTOR inhibitor

Anti-hormonal

Tamoxifen
Fulvestrant
Non-steroidal AIs : Letrozole, Anastrozole
steroidal AI : Exemestane
Megestrol acetate
Estrogen

Anti-hormonal

Chemotherapy


Anti-HER 2

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