harmesh naik, md. hope cancer clinic...tamoxifen and thus are unable to benefit from its...

Harmesh Naik, MD.Hope Cancer Clinic

A brief review of adjuvant therapy of breast cancer

Summarize selected new developments in adjuvant therapy of breast cancer

Discussion is limited to early stage breast cancer (non metastatic)

Reduce the risk of cancer recurrence

Improve overall survival

Improve/maintain quality of life and minimize long term toxicity –an important goal

Prevention of new cancer

Determine appropriate treatment based on risk

Determine risk of recurrence

Clinical trial evaluation Standard

therapy

•Aggressive therapy

•Chemotherapy, anti HER-2 therapy, combination therapy

High risk

•Low toxicity therapy

•Hormonal therapyLow risk

•Individualized

•Molecular markers, patient choiceInt risk

•Chemotherapy + Anti HER 2 based therapy (e.g. Trastuzumab)

HER2 positive

•Hormonal therapyER/PR

positive

•ChemotherapyER/PR neg

HER 2 neg

• AC-T, TAC, CAF, A-T-C

•Prefer dose denseNode positive, HER 2 negative

• All of above

• CMFNode negative, HER 2 negative

• AC-TH

• TCHHER 2 positive

• Tamoxifen

• Ovarian suppression if TAM is refused

Pre-menopausal

•AI agent (preferred)

•Tamoxifen (rarely)Post

menopausal

Patient 1 : A 51 yrs old, Right breast carcinoma, 4.5 cm. T2aN1a, IIB. One node positive. ER/PR strongly positive, HER-2 was +3 by IHC. What is the best systemic therapy option?

1. Systemic chemotherapy alone2. Systemic chemotherapy + Herceptin3. Herceptin alone4. Hormonal therapy alone5. Systemic chemotherapy + Herceptin + Hormonal therapy6. None

Chemotherapy + Herceptin + Hormonal therapy with an AI agent for 5 years.

S/P dose dense AC x 4 weekly Paclitaxel and Herceptin x 12 weekly Herceptin x 36 additional weeks.

Patient 2:

A 68 yrs old, right breast cancer,

Node positive T2N1, IIB

ER PR positive , HER 2 negative.

What is the best systemic therapy option?1. Systemic chemotherapy alone2. Systemic chemotherapy + Herceptin3. Hormonal therapy alone4. Systemic chemotherapy + Hormonal therapy 5. None

Chemotherapy + Hormonal therapy.

AC x 4 Paclitaxel x 4.

Patient 3 : A 61 year old female. Breast cancer, T2N0M0,

Stage IIA, pectoralis muscle involvement. Node negative. ER positive, HER-2 negative. What is the best systemic therapy option?

1. Systemic chemotherapy alone2. Hormonal therapy alone3. Systemic chemotherapy + Herceptin4. Systemic chemotherapy + Hormonal therapy5. None

Oncotype DX assay report indicated 10 year recurrence risk of 10% and recurrence score of 16.

Chemotherapy is not clearly indicated in this situation

Hormonal therapy alone (an AI agent) for 5 years

Biology of individual breast cancer as determined by gene expression determines clinical behavior and risk of cancer recurrence and thus, prognosis. This may allow individualized treatments based on unique genetic blueprint (genetic signature) of individual cancer Help identifying patients who are likely to respond to certain

treatments - choose specific treatment Help identifying patients who aren't likely to respond or tolerate

to certain treatment - minimize ineffective or toxic treatment and choose alternative treatment

Tamoxifen was an example of targeted therapy based on Estrogen receptor (ER) status

Risk assessment

(Prediction of outcomes)

Selection of best

treatment

Best outcome

Ross, J. S. et al. Oncologist 2008;13:477-493

Commercialized Multigene Predictors of Clinical Outcome for Breast Cancer

by

Jeffrey S. Ross et al in The Oncologist, Vol. 13, No. 5, 477-493, May 2008; doi:10.1634/theoncologist.2007-

0248

Oncotype DX (21 gene assay) Mammaprint (70 gene signature) Rotterdam Signature (76 gene assay) Many more are in development

There may be “too many” markers and methods creating confusion on optimal marker

Most of the new methods have yet to be validated in large prospective clinical trials

A 21 gene RT-PCR assay performed on formalin fixed paraffin embedded tissue

Recurrence score and % probability of recurrence

Identifies high risk patients who would benefit from chemotherapy and who would not

Helps select a group of patient who could avoid morbidity and cost of adjuvant chemotherapy

http://www.hhmi.org/biointeractive/

Already in use for node negative, ER positive patients to assess risk of recurrence and to determine need for chemotherapy

Cost is nearly $ 3000 (estimate)

PROLIFERATION

Ki-67

STK15

Survivin

Cyclin B1

MYBL2

ESTROGEN

ER

PR

Bcl2

SCUBE2

INVASION

Stromelysin 3

Cathepsin L2

HER2

GRB7

HER2

BAG1GSTM1

REFERENCE

Beta-actin

GAPDH

RPLPO

GUS

TFRC

CD68

16 Cancer and 5 Reference Genes From 3 Studies

Paik et al. N Engl J Med. 2004;351: 2817-2826

RS =

Coefficient x Expression Level

+ 0.47 x HER2 Group Score

- 0.34 x ER Group Score

+ 1.04 x Proliferation Group Score

+ 0.10 x Invasion Group Score

+ 0.05 x CD68

- 0.08 x GSTM1

- 0.07 x BAG1

Calculation of the Recurrence Score Result

Category RS (0-100)

Low risk RS <18

Int risk RS ≥18 and <31

High risk RS ≥31

Paik et al. N Engl J Med. 2004;351: 2817-2826

Soonmyung Paik, M.D et al: NEJM: 2004: Volume 351:2817-2826

http://content.nejm.org/content/vol351/issue27/images/large/07t1.jpeg

P < 0.00001 668 patients

Paik et al. N Engl J Med. 2004;351:2817-2826

High risk node negative group (Recurrence score over 31) appears to have similar risk of recurrence as node positive group

Paik et al. N Engl J Med. 2004;351:2817-2826

Soonmyung Paik, M.D et al: NEJM: 2004: Volume 351:2817-2826

http://content.nejm.org/content/vol351/issue27/images/large/07f4.jpeg

Node positive patients: traditionally gets chemotherapy

Retrospective analysis of SWOG 8814 study

Node positive, ER positive patients

40% were low risk by Oncotype DX (score <18)

CAF-T has no benefit over TAM alone in this group

Albain K et al: Lancet oncology: on line published on 12-10-2009.

Intermediate risk (score 18-30): no benefit of chemotherapy over Tamoxifen

High risk 31% patient (score over 31):Chemotherapy was beneficial (10 year DFS)

10 year OS in high risk: 68% for chemo versus 51 % for Tamoxifen

Replicated data in node positive patients

Need prospective studies

Low recurrence score patients: No benefit from chemotherapy

High recurrence score patients: Clear cut benefit from chemotherapy

Data for node positive subset is similar to prior node negative data by Paik et al.

Caution: Prospective data is still needed for node positive group

The Oncotype DX assay is recommended for use in newly diagnosed ER+, N- breast cancer patients to predict risk of recurrence. The assay can also be used to identify patients who may be successfully treated with tamoxifen and may not require adjuvant chemotherapy. “It has been suggested that tamoxifen-treated patients with an excellent estimated prognosis may be spared adjuvant chemotherapy.” Harris L et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol. 2007;25(33):5287-312.

“The option of using a gene-based assay of tumor tissue (Oncotype DX, Genomic Health) to help guide chemotherapy treatment decisions is now included within the systemic adjuvant treatment decision pathway for patients with node-negative or pN1mi (micrometastasis: 0.2 mm - 2.0 mm), hormone-receptor-positive, HER2-negative tumors that are 0.6 to 1.0 cm and moderately/poorly differentiated or with unfavorable features or > 1 cm.” NCCN Clinical Practice Guidelines in Oncology™ Breast Cancer, (Version 2.2008)

My practice: Reserve for HER negative, ER/PR positive, node negative

patients

Order Oncotype DX assay only if it is going to help in decision making.

Do not order the test if patient does not want chemotherapy regardless of results

Will now consider for selected node positive

ER receptor (ER-α66) predicts response to Tamoxifen (currently measured) About 40% ER positive tumors fail to respond to Tamoxifen ER –α 66 positive Tumors over expressing a variant ER-α36 are less likely to respond to Tamoxifen Alternative treatment strategy is needed (?AI agents, chemotherapy) for ER-α36 positive

L. Shi et al. JCO: 27: 3423-July 2009.

ER-α36, a Novel Variant of ER-α, is Expressed in ER-positive and -negative Human Breast Carcinomas.

Lisa Lee et al: Anticancer Res. 2008 ; 28(1B): 479–483.

ER-α36, a Novel Variant of ER-α, is Expressed in ER-positive and -negative Human Breast Carcinomas.

Lisa Lee et al: Anticancer Res. 2008 ; 28(1B): 479–483.

ER 36 positive

ER 36 positive

ER 66 negative

ER 66 negative

“Poor metabolizer” or “mutant CYP2D6” – low or completely deficient levels of CYP2D6 fail to activatetamoxifen and thus are unable to benefit from its antitumor effects Variants of CYP enzymes leads to poor metabolism of Tamoxifen and lower level of Endoxifen May be seen in up to 10% of Caucasians May predict lack of response to Tamoxifen

Clinical breast cancer: Vol 9 (4) Nov 2009: 214-215.

“Drugs can affect Tamoxifen metabolism Avoid strong or intermediate inhibitors of CYP2D6 –reduces Tamoxifen metabolism Testing for CYP2D6 is available Not yet recommended in NCCN guidelines Need prospective data

Strong inhibitors Paroxetine (Paxil) Fluoxetine (Prozac)

Intermediate inhibitors Sertraline Cimetidine Amiodorone Doxepin Ticlopidine Haloperidol

This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription Localized to chromosome 17 (in proximity of HER-2 gene TOP2A and HER-2 co amplification seen in 8% breast cancer

TOP2α may provide clues to who benefits from Anthracyclines

HER 2 positive cancers are considered more sensitive to Anthracycline based regimen BCIRG 006 data: Not conclusive. No diff between AC-TH or TCH MA 5 trial - Topo IIA amplification correlated with improved survival with Epirubicin (Pritchard et al: NEJM 354: 2103, 2006. CALGB 8541: topo IIA amplifications fail to predict response (L. Harris et al: JCO 27: 3430-2009) Conflicting data Need prospective data. Not ready for clinical use yet

Low rate of CR to neo-adjuvant therapy with AT or CMF in women with breast cancer and BRCA 1 mutation Intermediate CR rate with AC or FAC Higher CR rate after treatment with Cisplatin based regimens Need further studies

T. Byrski et al. JCO: 28: 375-2009.

A DNA microarray is a collection of microscopic DNA spots attached to a solid surface

A DNA microarray is also commonly known as gene chip, DNA chip, or biochip

DNA microarrays are created by robotic machines that arrange minuscule amounts of hundreds or thousands of gene sequences on a single microscope slide

DNA microarrays are used to simultaneously measure the expression of large numbers of genes.

Collect the messenger RNA molecules present in cells. Label each mRNA molecule by attaching a fluorescent dye. Place the labeled mRNA onto a DNA microarray slide. The messenger RNA will hybridize - or bind - to its complementary DNA on the microarray, leaving its fluorescent tag. Use a special scanner to measure the fluorescent areas on the microarray.

Figure accessed in 2010-http://en.wikipedia.org/wiki

Dr. Stuart Schreiber at http://www.hhmi.org/biointeractive/

•The thumbnail-sized devices are

microscopic grids that have pieces

of DNA representing every gene in

the human genome stuck on them.

•Scientists use them to measure

the activity of our 20,000-plus

genes at the same time.

Dr. Eric Lander at http://www.hhmi.org/biointeractive/

http://www.riken.go.jp/engn/r-world/info/release/news/2004/oct/image/frol_02l.jpg

Gene expression values from microarray

experiments are represented as heat maps to visualize the

result of data analysis.

Accessed in 2010-http://en.wikipedia.org/wiki

Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications Sørlie T et al. Proc National Acad Sciences 2001;98:10869-10874 doi: 10.1073/pnas.191367098 PNAS September 11, 2001 vol. 98 no. 19 10869-10874

Gene expression patterns of 85 experimental samples representing 78 carcinomas, three benign tumors, and four normal tissues, analyzed by hierarchical clustering using the 476

cDNA intrinsic clone set.

Sørlie T et al. PNAS 2001;98:10869-10874

Tumor subtypes

Full cluster ERB B2 cluster

Basal cell cluster

Normal like cluster

Luminal cluster

Comparison of experimental sample-associated dendrograms from two different hierarchical clustering analyses.


Overall and relapse-free survival analysis of the 49 breast cancer patients, uniformly treated in a prospective study, based on different gene expression classification.


Basal cell cluster

Luminal A cluster

CALGB 9344: AC versus AC-T in node positive high risk breast cancer (Henderson IC et al, JCO 21:976-983: 2003) Five biomarkers evaluated by IHC on tissue microarrays-ER, HER2, Ki-67, CK5/6, EGFR Formaldehyde fixed specimens 2151 patients with node positive cancers Patients were grouped in to 4 breast cancer subtypes

Nielsen TO et al: ASCO Bca symposium October 2009: Abstract 23.


Subtype ER HER2 KI 67 CK 5 or EGFR

Luminal A + - Low

Luminal B + + High

HER2 enriched

- +

Core basal - + +


Subtype No. pts Med RFS yrs

RFS (AC-Tvs AC)

P value

Luminal A 790 NR 1.04 0.73

Luminal B 340 11.13 0.69 0.018

HER2 enriched

221 9.08 0.57 0.0032

Core basal 444 8.93 0.75 0.0033

ER -ve, HER-2 -ve

557 0.8 0.07


Tumor subtypes identified by tissue microarray predicted prognosis Luminal A subtype had favorable outcome Basal or HER-2 enriched subtypes had poorer outcomes


Tumor subtypes identified by tissue microarray predicted benefit from Paclitaxel Core Basal subtype, HER-2 enriched subtype and Luminal B : improvement in RFS with Paclitaxel Luminal A: no benefit from paclitaxel Verified a prior subset analysis that ER+ , HER-2 neg group may not benefit form paclitaxel addition to AC


Docetaxel-Carboplatin-Trastuzumab versus AC-TH versus AC- T (began in 2001) Herceptin is indicated in HER 2 positive breast cancer with high risk features: e.g. ER/PR negative ER positive + Tumor size over 2 cm ER positive + Age less than 35 years ER positive +Nuclear grade 2 of 3

Herceptin prescribing information 2009

AC-TH TCH AC-T

Hazard ratio

Risk of rec

0.64

(36% reduction)

0.75

(25% reduction)baseline

DFS 65mon 84% 81% 75%

Heart failure 2%

21/1068 pts

0.4%

4 / 1056 pts

0.3%

7/1050 pts

Leukemia 7 pts 1 pt 2 pts

Slamon D et al: San Antonio breast conference

Clinical breast cancer: Vol 10 (1) Feb 2010: 19-26.

84

81

75

70

72

74

76

78

80

82

84

AC-TH DCH AC-T

5.5 yr DFS

TCH and AC-TH both are good adjuvant alternatives for HER 2 positive patients

Each regimen has pros and cons

AC-TH is slightly superior but appears more toxic

Individualize selection. Young patients: ? Favor AC-TH TCH provides an alternative to AC-TH in patients with increased

risk for cardiac toxicity or for those who wants less visits

NCCTG N 9831 clinical trial results

AC-T versus AC-T-H sequential versus AC+TH –concurrent

Concurrent arm has 25% improvement in DFS compared to sequential arm

AC-TH Concurrent is preferred regimen

Toxicity is not affected by this schedule

Dr. E. Perez-San Antonio Breast conference 2009

Clinical breast cancer: Vol 10 (1) Feb 2010: 19-26.

72

80

84

66

68

70

72

74

76

78

80

82

84

AC-T AC-T-H AC-TH

DFS at 5 years

Dr. E. Perez-San Antonio Breast conference 2009

Risk of breast cancer recurrence in Tamoxifen treated patients

15% at 5 years

33% at 15 years

Risk of recurrence continued beyond 5 years

(EBCTCG data Lancet 2005: 365: 1687)

Tamoxifen

Years 1-5

Extended LetrozoleYears 6-10

Tamoxifen

Years 1-5

Interval

1-3 years

Delayed extended Letrozole

Beneficial in pre menopausal women who becomes post menopausal on or after Tamoxifen

4 year DFS: 10.1% advantage in Letrozole group over placebo

Low risk node negative patients also benefited

Supports use of extended Letrozole for those who meet definition of post menopausal

Dr. P. Goss-San Antonio Breast conference 2009

Clinical breast cancer: Vol 10 (1) Feb 2010: 19-26

4 year DFS Diff in % Pre menopausal Post menopausal

All pts 10 3

Node positive 10 7

Node negative 11.5 1

4 yr distant DFS 5 2.5

Early pre-menopausal breast cancer: ER positive

“The addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival in premenopausal patients with estrogen-responsive early breast cancer”

an absolute reduction of 3.2 percentage points and a relative reduction of 36% in the risk of disease progression

Michael Gnant, M.D., NEJM: 2009: Volume 360:679-691

Disease free

Disease free

Distant mets

Distant mets

70 genes

78 p

atients

Gene expression profiling predicts clinical outcome of breast cancer : Laura J. van 't Veer, et al: Nature 415, 530-536(31 January 2002)

ER +ve signature

BRCA1 signature

BRCA1 negative

ER -ve signature

Gene expression profiling predicts clinical outcome of breast cancer : Laura J. van 't Veer, et al: Nature 415, 530-536(31 January 2002)

98 p

atients

38

ER

neg

550 ER reporter genes

100 BRCA 1 rep genes

harmesh naik, md. hope cancer clinic...tamoxifen and thus are unable to benefit from its...

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