Harmesh Naik, MD. Hope Cancer Clinic

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 risk of recurrence Determine appropriate treatment based on risk

Clinical trial evaluation Standard therapy

High risk Aggressive therapy Chemotherapy, anti HER-2 therapy, combination therapy Low risk Low toxicity therapy Hormonal therapy Int risk Individualized Molecular markers, patient choice

HER2 positive Chemotherapy + Anti HER 2 based therapy (e.g. Trastuzumab) ER/PR positive ER/PR neg HER 2 neg Hormonal therapy Chemotherapy

Node positive, HER 2 negative AC-T, TAC, CAF, A-T-C Prefer dose dense Node negative, HER 2 negative All of above CMF HER 2 positive AC-TH TCH

Pre-menopausal Tamoxifen Ovarian suppression if TAM is refused Post menopausal AI agent (preferred) Tamoxifen (rarely)

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 alone 2. Systemic chemotherapy + Herceptin 3. Herceptin alone 4. Hormonal therapy alone 5. Systemic chemotherapy + Herceptin + Hormonal therapy 6. 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 alone 2. Systemic chemotherapy + Herceptin 3. Hormonal therapy alone 4. 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 alone 2. Hormonal therapy alone 3. Systemic chemotherapy + Herceptin 4. Systemic chemotherapy + Hormonal therapy 5. 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

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

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

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)

16 Cancer and 5 Reference Genes From 3 Studies PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 INVASION Stromelysin 3 Cathepsin L2 ESTROGEN ER PR Bcl2 SCUBE2 GSTM1 CD68 BAG1 HER2 GRB7 HER2 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC Paik et al. N Engl J Med. 2004;351: 2817-2826

Calculation of the Recurrence Score Result 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 Category RS (0-100) - 0.07 x BAG1 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

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

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 36 positive ER 66 negative ER 36 positive ER 66 negative 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.

Poor metabolizer or mutant CYP2D6 low or completely deficient levels of CYP2D6 fail to activate tamoxifen 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

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

Sørlie T et al. PNAS 2001;98:10869-10874 Overall and relapse-free survival analysis of the 49 breast cancer patients, uniformly treated in a prospective study, based on different gene expression classification. Luminal A cluster Basal cell 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. Clinical breast cancer: Vol 9 (4) Nov 2009: 213-214.

Subtype ER HER2 KI 67 CK 5 or EGFR Luminal A + - Low Luminal B + + High HER2 enriched - + Core basal - + + Clinical breast cancer: Vol 9 (4) Nov 2009: 213-214.

Subtype No. pts Med RFS yrs RFS (AC-T vs 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 Clinical breast cancer: Vol 9 (4) Nov 2009: 213-214.

Tumor subtypes identified by tissue microarray predicted prognosis Luminal A subtype had favorable outcome Basal or HER-2 enriched subtypes had poorer outcomes Clinical breast cancer: Vol 9 (4) Nov 2009: 213-214.

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 Clinical breast cancer: Vol 9 (4) Nov 2009: 213-214.

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 0.75 (36% reduction) (25% reduction) baseline DFS 65mon 84% 81% 75% Heart failure 2% 0.4% 0.3% 21/1068 pts 4 / 1056 pts 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 84 82 81 80 78 76 74 72 70 AC-TH DCH AC-T 75 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.

84 82 80 78 76 74 72 70 68 66 84 80 72 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 Tamoxifen Years 1-5 Extended Letrozole Years 6-10 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

78 patients 70 genes Disease free Distant mets Disease free Distant mets Gene expression profiling predicts clinical outcome of breast cancer : Laura J. van 't Veer, et al: Nature 415, 530-536(31 January 2002)

98 patients 550 ER reporter genes ER +ve signature ER -ve signature 38 ER neg 100 BRCA 1 rep genes BRCA1 signature BRCA1 negative Gene expression profiling predicts clinical outcome of breast cancer : Laura J. van 't Veer, et al: Nature 415, 530-536(31 January 2002)