Frédérique Penault Llorca : Oncotype DX® Breast Cancer Assay: Results and Impact on Treatment Decisions. The French experience

Oncotype DX® Breast Cancer Assay: Results and Impact on Treatment Decisions

The French experience

Frédérique Penault-‐Llorca

The Recurrence Score® Result Uses Key Genes Linked to CriEcal Molecular Pathways

16 BREAST CANCER RELATED GENES

ER PR Bcl2

SCUBE2

GRB7 HER2

Ki-‐67 STK15 Survivin Cyclin B1 MYBL2

Stromelysin 3 Cathepsin L2

GSTM1

CD68

BAG1

Beta-‐acKn GAPDH RPLPO GUS TFRC

5 REFERENCE GENES

Estrogen ProliferaKon HER2 Invasion Others

Paik S, et al. N Engl J Med. 2004;351:2817-‐2826. 2

The Recurrence Score® Result Has Demonstrated Clinical Validity in Numerous Landmark Studies •  NSABP B-‐14: The Oncotype DX® Assay Is PrognosEc of

Distant Recurrence in Tamoxifen-‐Treated PaEents

3 10-‐Year rate of recurrence = 30.5% for High RS vs 6.8% for Low RS, p<0,001

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

The Recurrence Score® Result Has Demonstrated Clinical Validity in Numerous Landmark Studies •  NSABP B-‐20: Only the Oncotype DX® Assay is Currently Validated to Predict

Benefit From Chemotherapy

4

PATIENTS WITH HIGH RECURRENCE SCORE® RESULT 28% absolute benefit from tamoxifen + chemotherapy

4.4% absolute benefit from tamoxifen + chemotherapy

Paik S, et al. J Clin Oncol. 2006;24:3726-‐3734.

The Recurrence Score® Result Has Demonstrated Clinical Validity in Numerous Landmark Studies

•  SWOG 8814: Breast Cancer-‐Specific Survival of Node-‐PosiEve PaEents by Treatment and Recurrence Score® Group

5

No benefit to CAF over Kme for low Recurrence

Score

High benefit to CAF over Kme for high

Recurrence Score

Albain KS, et al. Lancet Oncol. 2010;11(1):55-‐65.

The Recurrence Score® Result Has Demonstrated Clinical Validity in Numerous Landmark Studies •  Validated results from well designed randomized cooperaEve group

clinical trials in homogenous paEent populaEons

PrognosKc for distant recurrence and predicKve for

treatment benefit

6

The Oncotype DX® Assay Provides Reproducible Results in Relevant PaEents Across a ConEnuum of ER+ Breast Cancer

Study ClassificaKon Randomized Clinical Trial

Protocol-‐Specified Treatment

Clinical Outcome Assessed

NSABP B-‐14 (2004)

ValidaKon/ Confirmatory X X 10-‐year distant recurrence rate (6.8%, 14.3%, 30.5% for low,

intermediate, high Recurrence Score® risk groups)

Gianni (2005) SupporKve X Pathologic complete response to neoadjuvant chemotherapy (high Recurrence Score was associated with higher likelihood of pCR; P = 0.005)

NSABP B-‐20 (2006)

ValidaKon/ Confirmatory X X

10-‐year distant recurrence rate (risk reducEon from the addiEon of chemotherapy in the high-‐risk group; no demonstrable relaEve risk reducEon in the low-‐risk group (0.26 vs 1.31))

Kaiser (2006) ValidaKon/ Confirmatory

10-‐year risk of breast cancer death (2.8%, 10.7%, 15.5% for low-‐, intermediate-‐, and high-‐risk groups)

Chang (2007) SupporKve X Clinical complete response to neoadjuvant chemotherapy (> 1.7-‐fold increase for paEents with high vs low score)

ECOG 2197 (2008) SupporKve X X

11.5-‐year disease-‐free recurrence (score was a significant predictor of recurrence including node-‐negaEve and node-‐posiEve disease; P < 0.0001)

Akashi-‐Tanaka (2009) SupporKve X 5-‐year recurrence-‐free survival (100%, 84%, and 73% for low-‐,

intermediate-‐, and high-‐risk groups)

SWOG 8814 (2010)

ValidaKon/ Confirmatory X X

10-‐year disease-‐free survival (60% vs 43% for low-‐ vs high-‐risk groups); 10-‐year breast cancer specific survival (low 92% T vs 87% CAF-‐T and high 54% T vs 73% CAF-‐T; test for interacEon between score and treatment P = 0.021)

Burke E, et al. Poster at St. Gallen Intn. Breast Cancer Conference. 2013. 7 Burke E, et al. Poster at St. Gallen Intn. Breast Cancer Conference. 2013.

The Oncotype DX® Assay Provides Reproducible Results in Relevant PaEents Across a ConEnuum of ER+ Breast Cancer (Cont.)

Study ClassificaKon Randomized Clinical Trial

Protocol-‐Specified Treatment

Clinical Outcome Assessed

TransATAC (2010) ValidaEon/ Confirmatory X X

9-‐year distant recurrence (4%, 12%, and 25% in low-‐, intermediate-‐, and high node-‐negaEve risk groups, 17%, 28%, and 49% in node-‐posiEve risk groups)

Toi (2010) ValidaEon/ Confirmatory

10-‐year distant recurrence risk (3.3% , 0%, 24.8% for low-‐, intermediate-‐, high-‐risk node-‐negaEve groups; low vs high P < 0.001)

Masuda (2001) SupporKve X Clinical response to neoadjuvant hormonal therapy (59%, 59%, 20% for low-‐, intermediate-‐, and high-‐risk groups)

Yardley (2011) SupporKve X Pathologic complete response to neoadjuvant chemotherapy (0%, 0%, 26% for low-‐, intermediate-‐, and high-‐risk groups; Mantel-‐Haenzel χ2 P = 0.002)

NSABP B-‐28 (2012) SupporKve X X 10-‐year distant recurrence-‐free interval (75.8%, 57.0%, and 48.0% for

low-‐, intermediate-‐, and high-‐risk groups); P < 0.001)

Burke E, et al. Poster at St. Gallen Intn. Breast Cancer Conference. 2013. 8

13 studies that included > 5,700 paEents (>3,400 node-‐negaEve and >2,080 node-‐posiEve)

Burke E, et al. Poster at St. Gallen Intn. Breast Cancer Conference. 2013.

The Oncotype DX® Assay

The Only MulE-‐gene Assay Incorporated into 4 Major Guidelines to Predict Adjuvant

Chemotherapy Benefit in ER+, HER2-‐ Early Stage Breast Cancer

1 NCCN PracEce Guidelines in Oncology. V.3.2013. 2 Harris L, et al. J Clin Oncol. 2007. 3 Goldhirsch A, et al. Ann Oncol. 2013. 4 NICE DiagnosEcs Guidance 2013.

ASCO® Guidelines Node negaKve

NCCN Guidelines® > 0.5 cm, node negaKve, N1mi

St Gallen Consensus Node negaKve, node posiKve

QuanKfies risk of recurrence as a conKnuous variable and predicts responsiveness to both tamoxifen and chemotherapy1

Provides not only prognosKc but also predicKve informaKon regarding the uKlity of cytotoxic therapy in addiKon to

endocrine therapy3

9

NICE Node negaKve

Recommended as an opKon for guidance of chemotherapy decisions in paKents at intermediate risk* of distant recurrence4

ASCO is a trademark of the American Society of Clinical Oncology. NCCN and NCCN Guidelines are trademarks of the NaEonal Comprehensive Cancer Network. The guidelines do not endorse products or therapies. *Intermediate risk of distant recurrence is defined as Nomngham PrognosEc Index score above 3.4 or being at intermediate risk by other decision making tools or protocols

Predicts the risk of recurrence and may be used to idenKfy paKents likely to benefit from tamoxifen or chemotherapy2

Oncotype DXTM assay in rouKne pracKce

•  FFPE samples •  Fill the form •  Send a block or blank slides •  Results within 8 working days by email

In France….

•  No reimbursement so far! – Impact study – Medico-‐economic study – Regional iniEaEves – Results from my insEtuEon

IMPACT STUDY

ProspecKve Study of the Impact of using the 21-‐Gene Recurrence Score Assay on Clinical Decision Making in Women with Estrogen Receptor-‐posiKve, HER2-‐negaKve, Early

Stage Breast Cancer in France

Gligorov J, Pivot XB, Naman HL, Jacot W, Spaeth D, Misset JL, Largillier R, SauEere JL, de Roquancourt A, Pomel C, Rouanet P,

Rouzier R, Penault-‐Llorca FM for the Francilian Breast Intergroup

13

Overall Impact of the Oncotype DX Assay on Treatment RecommendaEons

(n=96)

60% 40%

Treatment recommendation prior to

Oncotype DX assay Recommendation after

Oncotype DX assay Recommendation after

Oncotype DX assay

Chemotherapy

No Chemotherapy

n = 30 n = 20 n = 15

89% 11%

n=41 n=5

14

36% of paKents (95% CI: 27%-‐47%) had a change in treatment recommendaKon; 5 (5%) added chemotherapy and 30 (31%) removed chemotherapy.

The proporKon of paKents recommended chemotherapy decreased from 52% pre-‐Oncotype DX assay to 26% post-‐Oncotype DX assay (p<0.001 for McNemar’s test).

Metaanalysis of 9 clinical uElity studies (7 retrospecEve, 2 prospecEve) with total n=1154 ER+, N0 EBC paEents

42%58%

Chemo + hormonal therapy

Hormonal therapy only

Overall, the RS led to a 36% change in treatment decisions •  30% from CT+HTà HT •  6% from HT à CT+HT

Hornberger J, et al. St. Gallen 2011. #P201.

6% change

RecommendaKon aoer RS in paKents with

iniKal HT recommendaKon

Treatment plan before the Oncotype DX breast cancer assay

30% change

RecommendaKon aoer RS in paKents with

iniKal CHT recommendaKon

Conclusions: •  These are the first prospecEve data regarding the impact of using the Oncotype DX assay in France.

•  The adjuvant treatment recommendaEon changed in 36% of the paEents arer receiving the Recurrence Score result, predominantly from chemoendocrine to endocrine treatment alone.

•  The proporEon of paEents recommended chemotherapy decreased from 52% to 26% post-‐Oncotype DX assay (p<0.001). – There was a large proporEon of paEents with lobular and grade II tumors and a higher rate of low and intermediate risk paEents compared to previously reported clinical datasets.

16

Conclusions

•  There was a significant improvement in physician confidence arer receiving the Recurrence Score result (signed rank test p<0.001).

•  Physicians agreed or strongly agreed that the Oncotype DX assay results provided addiEonal informaEon in 79% of paEents (95% CI: 69%-‐87%) .

•  The results from the study are consistent with data from studies in other countries.

Impact of the Oncotype DX® Breast Cancer Assay in N0, ER+ EBC

ProspecEve Decision Impact Studies from Various Countries

#1-‐3 posiEve lymph nodes, HT only endocrine therapy, CHT chemoendocrine therapy 1Lo S, et al. J Clin Oncol. 2010. 2Albanell et al. Ann Oncol 2011, 3Eiermann et al. Ann Oncol 2012 in press, 4Yamauchi et al. ESMO 2011,

5De Boer et al. SABCS 2011, 6Davidson JA et al. ASCO 2012, 7Holt S et al., St. Gallen 2011, #P196, 8Gligorov J et al. ASCO 2012

Study N Change rate from pre-‐ to post-‐Oncotype DX® breast

cancer assay

CHT to HT

HT to CHT

US Study1 (N0) 89 31.5% 22.5% 3.4%

Spanish Study2 (N0) 107 31.8% 20.6% 11.2%

German Study3 (N0) 244 30.3% 18.4% 11.5%

Japanese Study4 (N0) 73 30.1% 27.4% 2.7%

Australian Study5 (N0) 101 22.8% 11.9% 10.9%

Canadian Study6 (N0) 150 30% 20% 10%

UK Study7 (N0, N1itc, N1mic) 142 26.8% 18.3% 8.5%

French Study8 (N0, N1mic) 96 36% 31% 5%

Impact of the Oncotype DX® Breast Cancer Assay Decision Impact Studies from Various Countries (N0 and N+)

#1-‐3 posiEve lymph nodes, HT only endocrine therapy, CHT chemoendocrine therapy 1Lo S, et al. J Clin Oncol. 2010. 2Albanell et al. Ann Oncol 2011, 3Eiermann et al. Ann Oncol 2012 in press, 4Yamauchi et al. ESMO 2011,

5De Boer et al. SABCS 2011, 6Davidson JA et al. ASCO 2012, 7Holt S et al., St. Gallen 2011, #P196, 8Gligorov J et al. ASCO 2012

Study N Change rate from pre-‐ to post-‐Oncotype DX® breast

cancer assay

CHT to HT

HT to CHT

US Study1 (N0) 89 31.5% 22.5% 3.4%

Spanish Study2 (N0) 107 31.8% 20.6% 11.2%

German Study3 (N0) 244 30.3% 18.4% 11.5%

Japanese Study4 (N0) 73 30.1% 27.4% 2.7%

Australian Study5 (N0) 101 22.8% 11.9% 10.9%

Canadian Study6 (N0) 150 30% 20% 10%

UK Study7 (N0, N1itc, N1mic) 142 26.8% 18.3% 8.5%

French Study8 (N0, N1mic) 96 36% 31% 5%

German Study3 (N+#) 122 38.5% 27.9% 9.0%

Japanese Study4 (N+#) 17 70.6% 70.6% 0%

Australian Study5 (N+#) 50 26% 24% 2%

COST STUDY

Cost of adjuvant chemotherapy in France

•  RetrospecEve study conducted in Tenon hospital

•  Average cost of chemotherapy per paEent: –  To the society: €14,835 –  To the social security (NHS): €13,474

Cost study in France

•  Average cost of chemotherapy per paEent: ▫  To the society: €14,835 ▫  To the social security (NHS): €13,474 •  Chemotherapy drugs represent 40-‐43% of the total cost •  Very conservaEve esEmate of the cost of chemotherapy as the costs following the full chemotherapy regimen are not taken into account: ▫  Follow-‐up visits ▫  Long term adverse events ▫  Absenteeism arer chemotherapy regimen

Cost-‐effecEveness results in case of use of OncotypeDX®

Per paKent tested Usual care Oncotype DX® Difference

Discounted cost €11,804 €11,174 € 629

Discounted Life Years

13.21 13.33 0.13

Incremental Cost-‐effecEveness RaEo

-‐ -‐ Cost-‐savings

•  Expected increased Life years when treatment decisions are informed by Oncotype DX® (paEents reclassified towards chemotherapy arer recurrence score)

•  Decreased overall cost when treatment decisions are informed by Oncotype DX® (decreased chemotherapy costs for paEents who are spared un-‐necessary chemotherapy)

à Using Oncotype DX® in the French setng is expected to be cost-‐savings

Consistent cost-‐effecEveness results regardless of country and local cost data

PublicaKon Reported Findings (ICER in Cost per QALY gained with Oncotype DX)

Country Threshold (Willingness to pay for 1 QALY($))

Country Comment

Lacey L et al. 2011 EUR 9,462 EUR 20,000 Ireland Cost EffecKve

Holt et al. 2011 GBP 6,232 GBP 20,000 UK Cost EffecKve

Klang et al. 2010 USD 10,700 USD 35,000 Israel Cost EffecKve

Tsoi et al. 2010 USD 63,421 USD 75,000 Canada Cost EffecKve

Paulden et al. 2011 > USD 29,000 USD 75,000 Canada Cost EffecKve

Kondo et al. 2010 USD 3,848 USD 50,000 Japan Cost EffecKve

Madaras et al. 2011 USD 14,110 USD 20,000 Hungary Cost EffecKve

O’Leary et al. 2010 AUS 9,986 AUS 18,000 Australia Cost EffecKve

de Lima Lopez et al. 2011 Improved outcomes (QALYs), reduced costs

Singapore Cost Savings

Chereau et al, SABC 2011 France Cost Savings

Hornberger et al. 2005 USA Cost Savings

Lyman et al. 2007 USA Cost Savings

Regional iniEaEves

Experience from X Pivot’s team Study flow chart

Cas$de$pa(entes$$discutés$en$RCP$de$valida(on$de$tests$biologiques$pour$la$

réalisa(on$de$Oncotype$DX®$N$=$62$

Cas$analysés$N$=$51$(82%)$

Cas$sélec(onnés$pour$la$réalisa(on$de$Oncotype$DX®$N$=$52$(84%)$

Résultats$N$=$48$(77%)$

10$cas$non$retenus$(16%)$

1$cas$$non$analysable$(2%)$$

3$cas$avec$décision$thérapeu(que$non$guidée$par$

Oncotype$DX®$(5%)$

Cas$de$pa(entes$$discutés$en$RCP$de$sénologie«$cancer$du$sein$localisés$»$$

N=$1592$1530$cas$non$retenus$pour$la$réalisa(on$de$Oncotype$DX®$

(96%)$

Figure$1$:$Flow%Chart%pour$la$réalisa(on$de$Oncotype$DX®$

Nerich et al, Bull du Cancer 2014

Recurrence Score Figure'2':'Répar..on'du'Recurrence'Score'(RS)'par'pa.entes'

0'

5'

10'

15'

20'

25'

30'

35'

40'

45'

50'

55'

60'

65'

0' 1' 2' 3' 4' 5' 6' 7' 8' 9' 10'11'12'13'14'15'16'17'18'19'20'21'22'23'24'25'26'27'28'29'30'31'32'33'34'35'36'37'38'39'40'41'42'43'44'45'46'47'48'

Pa.entes'

Valeu

r'du

'Recurrence'Score'

RS'faible'

'RS'interE'

Eméd

iaire'

RS'élevé'


Cost effecKveness Cost (€) by expenditure «Oncotype DX®»

Strategy

«Standard»

Strategy

DifferenKal

Chemotherapy 20 559 75 911 -‐55 352

implantable chamber 13 928 51 425 -‐37 497

Biology tests 1 039 3 836 -‐2 797

PegfilgrasKm (drug + injecKon) 1 936 7 147 -‐5 211

Hairpiece 1 625 6 000 -‐4 375

Transport 4 527 16 716 -‐12 189

Oncotype DX® Test 111 300 / +111 300

Total coost for 48 paKentes 154 914 161 035 -‐6 121

By paKent 3 227 3 355 -‐128


EXPERIENCE FROM MY INSTITUTION

Centre Jean Perrin’s cases

•  From 2011 to 2014 •  57 pts – Median size : 1,9 (0,4 to 4 cm) –  51 SBR grade II, 6 grade I, no grade III – All ER Allred 8 or 9, 11 PR negaEve or low –  30 High Ki67, 12 with vascular embolies –  21 N+

•  Recurrence score : 39 Low RS, 13 Intermediate RS, 3 High RS, 2 NI

•  9 paKents received CT

Conclusions

•  Results of decision impact studies are very consistent across different countries -  ~30% change in treatment recommendaKons aoer Oncotype DX® for node

negaKve paKents, and clinically relevant also in node-‐posiKve disease

-  Treatment recommendaKons followed the Recurrence Score result

-  Intermediate Recurrence Score also provides clinically relevant informaKon

-  Use of the Recurrence Score result led to a clinically significant reducKon in chemotherapy use

•  Cost effecKveness is demonstarted in different models •  TesKng with Oncotype DX® increased confidence of physicians in adjuvant

therapy decision-‐making (N0 and N+)

Health & Medicine

Frédérique Penault Llorca : Oncotype DX® Breast Cancer Assay: Results and Impact on Treatment Decisions. The French experience