Affinitor in bc

"Targeted" Therapy for Advanced Breast Cancer

"Affinitor"

Aumkhae Sookprase!, MD

ศูนย์มะเร็งอุดรธานี22 พย 2556

Friday, November 22, 2013

(Early stage breast cancer)

(Locally advanced 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


HER 2

E

THE "MUST" HAVE IHC IN EVERY BREAST CANCER

Ki-67

HER2 positive = 3+

ER positive = at least 1% staining


ER and PR and HER2 negative

ER and/or PR positive and HER2 negative

HER 2 +, ER / PR -

Triple negative(TN)

Luminal A / B HER 2


ER and PR and HER2 negative

Chemotherapy

Triple negative tumor


HER 2 +, ER / PR -

Anti-HER 2

HER2 positive tumor


HER 2 positive breast cancer

Normal cell


ER and/or PR positive and HER2 negative

Anti-hormonal

ER positive tumor


Growth of cancer cells


Surgery

Chemotherapy4 - 6 cycles every 3 weeks

Radiation( size > 5 cms, lymph node involvement)

(ER and PR and HER2 negative)Basal subtype


Surgery

Chemotherapy

Radiation( size > 5 cms, lymph node

involvement)

(ER negative and HER2 negative)HER 2 subtype

Anti- HER 2 (Trastuzumab )

1 yr

+


Surgery

Chemotherapy

Radiation( size > 5 cms, lymph node

involvement)

(ER positive and HER2 negative)Luminal subtype

Anti-hormonal 5 yrs

+ / -


Nucleus

Growth & proliferation

Methods to inhibit ER in Early Stage

TAMOXIFEN

1. NS-AIs : LET, ANA

2. S-AI : EXE

Post-menopausal


2. Type of distant metastasis

1.Bone metastasis2.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 status2. Tumor's factor : Biology (tumor subtype)3. Treatment's goal - Rapid response in patient with widespread metastasis - Toxicity profiles in each treatment


FAC

Taxanes

Capecitabine

Vinorelbine

Gemcitabine IxabepiloneEribulin

Chemotherapy


Trastuzumab Lapatinib

Anti-HER 2


58% ER positive tumors 1

1Lertsanguansinchai P, et al. J Med Assoc Thai. 2002

HR+58%

Anti-hormonal is a mainstay treatment


Anti-hormonal

TamoxifenFulvestrant

Non-steroidal AIs : Letrozole, Anastrozolesteroidal AI : Exemestane

Megestrol acetateEstrogen

Chemotherapy

Anti-hormonal

Anti-HER 2


Nucleus


Methods to inhibit ER

TAMOXIFEN


2. S-AI : EXE

OFS

(GnRH or surgical)

Pre-menopausal

Post-menopausal

FULVESTRANT


(survival) QoL

Factors

1. Patient's factor : Performance status2. Tumor's factor : Biology (tumor subtype)3. Treatment's goal - Rapid response in patient with widespread metastasis - Toxicity profiles in each treatment


HR + MBC

Life-treatening HR+ MBC Non - life-treatening HR+ MBC

1st line CT

2 nd line CT

3 rd line CT

4 th line CT

Later line of CT

PD

PD

PD

PD

Response

1 st line Maintenance HTPD

Response2 nd line

Maintenance HTPD

Response 3 rd line Maintenance HT

PD

Response4 th line

Maintenance HT


HR + MBC

Life-threatening HR+ MBC Non - life-threatening HR+ MBC

1st line CT

2 nd line CT

3 rd line CT

4 th line CT

Later line of CT

1 st line HT

2 nd line HT

3 rd line HT

4 th line HT

Later line HT

PD with life - threatening metastasis

Response

Not response


Early Stage Metastatic setting


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

Tamoxifen (1977)

Letrozole (1997)

Fulvestrant (2002)

1970 1975 1980 1985 1990 1995 2000 2005 2010 2015

Exemestane (1999)

Anastrozole (1995)

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.Friday, November 22, 2013

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


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


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.


Nucleus


Methods to inhibit ER

TAMOXIFEN


2. S-AI : EXE

OFS

(GnRH or surgical)

Pre-menopausal

Post-menopausal

FULVESTRANT


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

Initial Second N ORR (%) CBR(%) TTP (months)A or L

EAEA

A or LA or LA or LA or LA or L

Mostly A or L

E 23 8.7 43.5 5.1A or L 18 22.2 55.6 9.3

E 12 - - 4.4A 11 - - 1.9E 50 8 44 5E 114 5 46 4E 31 19.4 54.8 3.2E 30 0 46.6 4E 60 20 38.3 3.2E 105 4.8 20 3.2E 5 - 20 50 3 - 5


Modest Benefit of Single-Agent Chemotherapy for Advanced BC

Typical Clinical OutcomesTypical 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 dataLimited 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


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

HR+ Advanced Breast Cancer

E


Mechanisms of AI resistance



A. Ineffective inhibition of AIs



B. Alternative sources of E



D. Ligand-independent

activation of E-signaling pathways


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

Src

PP

P PER

CoAERCoA

PCoA

PI3K

AKT

Ras

MAPK

ERP

P P

PERS6KI

ERCoA

mTORE

HER2, FGFR, EGFR, IGF-1R

HR+ Advanced Breast Cancer


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 endocrine-resistant 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):S28-S36.


Potential Therapeutic Target to Overcome Resistance of

NS-AIs


"Targeted" Therapy for Advanced Breast Cancer

"Affinitor"

Aumkhae Sookprase!, MD

ศูนย์มะเร็งอุดรธานี22 พย 2556


NEJM, Feb, 2012.


DFS


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

Tamoxifen (1977)

Letrozole (1997)

Fulvestrant (2002)

Everolimus + exemestane

(2012)

1970 1975 1980 1985 1990 1995 2000 2005 2010 2015

Exemestane (1999)

Anastrozole (1995)

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


Aphthous like ulcers, discrete, well-demarcated with whitish pseudomembrane

Typically develop acutely in the first cycle

Severity peak within 2 weeks of treatment

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


Acne inform dermatitis

Start with inflammatory lesion, papule, macule

Distribute over and un-usual areas : upper extremities, trunk, neck

Rash : Clinical manifestation ( all grade 39%, grade 3 : 8%)


Obtain base line CXR

"diffuse ground glass or patchy infiltration"

Non-infectious pneumonitis : Radiographic ( all grade 16%, grade 3 : 3%)


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 Investigation Management Everolimus Dose

Grade 1CT scans with lung windowsRepeat at least every 12 weeks until return to within normal limits

No specific therapy 100%

Grade 2

CT scans with lung windowsRepeat at least every 12 weeks until return to within normal limitsConsider PFTb

Consider bronchoscopy with biopsy and/or BAL

Symptomatic onlyCorticosteroids if symptoms are troublesome

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

Grade 3

As for grade 2 with PFTRepeat at least every 6 weeks until return to within normal limitsBronchoscopy with biopsy and/or BAL recommendedExclude infection/progression of underlying malignancy

Corticosteroids if of noninfectious originTaper as indicated

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

Grade 4 As for grade 3 As for grade 3 Discontinue everolimus


BOLERO-2 : Most Common Adverse Events


Anti-hormonalReverse or delay resistance

mTOR inhibitor TamoxifenFulvestrant

Non-steroidal AIs : Letrozole, Anastrozolesteroidal AI : Exemestane

Megestrol acetateEstrogen

Chemotherapy

Anti-hormonal

Anti-HER 2


Affinitor in bc

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