Can we use multigene-tests to guide the adjuvant treatment of early breast cancer?

R5 陳三奇VS 趙大中

J Natl Compr Canc Netw 2013;11:174-182 J

• Breast cancer– A heterogeneous disease– Outcome predict by clinical and pathologic

features.– Genomic tests since 2002• Oncotype DX, PAM50, and MammaPrint.• Others: Rotterdam 76-gene signature, 3-gene

SCMGENE panel– The role of these multigene tests ?

NSABP B-14 、B-20 trial 10 years follow up

• Early breast cancer with ER(+) and LN (-)

• NSABP B-14 trial (National Surgical Adjuvant Breast and Bowel Project clinical trial B-14. )– Randomly assigned to placebo (n=1453) or tamoxifen (n=1439)– Recurrent free survival :hazard ratio 0·58 (95% CI 0·50–0·67, p<0·0001)– Overall survival: HR 0·80, (95% CI 0·71–0·91, p=0·0008)

• NSABP B-20 trial– Randomly assigned to tamoxifen (n=788) or cyclophosphamide,

methotrexate, fluorouracil, and tamoxifen (CMFT, n=789)– Rcurrence-free survival 0·52 ( 0·39–0·68,p<0·0001) – Overall survival 0·78, (0·60–1·01, p=0·063)

Fisher et al. Lancet 2004; 364: 858–68

NSABP B-14 NSABP B-20

Fisher et al. Lancet 2004; 364: 858–68

CMFT

Placebo

Tamo

Fisher et al. Lancet 2004; 364: 858–68

• Conclusions of NSABP B-14 and B-20 trial 10 years follow up: – 1. Tamoxifen has much benefit in ER(+) and LN (-) patients.– 2. Older women tend to have higher tumor oestrogen-receptor

concentrations and are more likely to benefit from tamoxifen than from chemotherapy; in younger women, the converse is true

CMFT

Tamo

Placebo

Fisher et al. Lancet 2004; 364: 858–68

Oncotype DX• Oncotype DX score: – Quantitative reverse transcriptase polymerase chain reaction

(RT-PCR)– measures 21 genes in formalin-fixed paraffin-embedded

breast tumors.

Oncotype DX to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer

• Retrospective analysis of 668 tumor blocks in NSABP –B14 trial– ER (+), LN (-), Tamoxifen-treated

Paik et al. N Engl J Med 2004;351:2817-26

Low v.s. high-risk groups (6.8% vs. 30.5; P<.001)

• Conclusion of Oncotype DX for NSABP B-14 trial: – The RS quantified the likelihood of distant recurrence in tamoxifen-treated

patients with ER(+), LN(-) breast cancer.

Paik et al. N Engl J Med 2004;351:2817-26

Oncotype DX to Predict Death of Node-Negative Breast Cancer

• A case-control study– N= 4969 – Node-negative, EBC from 1985 to 1994, not treated with adjuvant chemotherapy.– 220 patients died from breast cancer.

• Treated with tamoxifen, the death rate was– Low risk: 2.8 %– Intermediate risk: 10.7% – High risk :15% (P=.003).

• Not treated with Tamoxifen for ER(+) patients, the death rate was– Low risk: 6.2%. – Intermediate risk: 17.8% – High risk :19.9%

• Conclusion: – The RS strongly associated with risk of breast cancer death among ER-positive,

tamoxifen-treated and untreated patients.

Habel et al. Breast Cancer Research 2006, 8:25

• The 21-gene recurrence score (RS) assay – quantifies the likelihood of distant recurrence in women with

• ER (+), LN (-), treated with adjuvant Tamoxifen. – Strongly related to cancer death in

• ER (+), LN (-), treated with or without Tamoxifen.

• Suggest that– combining Recurrence Score, tumor grade, and tumor size

provides better risk classification than any one of these factors alone.

• However, the relationship between the RS and chemotherapy benefit is not known.

Oncotype DX to Predict Recurrence of Tamo or CMF-treated,LN(-), ER (+) Breast Cancer

• Retrospective analysis of the RS in – NSABP B-20– LN (-), ER (+), – Treated with

tamoxifen or Tamoxifen plus chemotherapy (CMF-T)

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

Low risk

Int. risk High risk

• Conclusions: – High risk patients experienced a significant benefit from

chemotherapy , whereas low risk patients had no benefit.

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

Oncotype DX to Predict DFS and OS of postmenopausal , ER(+), LN(+) treated with CT

• SWOG-8814, INT-0100– Postmenopausal women, ER (+), LN (+)– Randomized into 3 group for adjuvant therapy :

• Tamoxifen• CAF-T

(cyclophosphamide, doxorubicin, and fluorouracil x 6 cycles, Tamoxifen for 5 years)

• CAFT

• Results: – CAF-T or CAFT was superior to Tamoxifen for DFS, and

marginally for OS.– Adjusted HRs favoured CAF-T over CAFT.

KS el tl.Lancet. 2009 Dec 19;374(9707):2055-63

•Retrospective analysis the recurrence score on DFS by treatment group (tamoxifen vs CAF-T)

N= 367 specimens, tamoxifen, n=148; CAF-T, n=219.

Albain et al. Lancet Oncol 2010; 11: 55–65

Tamoxifen alone

Oncotype DX to Predict DFS and OS of postmenopausal , ER(+), LN(+) treated with CT

Low risk group

Int. risk group High risk group

All patients

Disease free survival Albain et al. Lancet Oncol 2010; 11: 55–65

Low risk group Int. risk group

High risk group

Overall survival Albain et al. Lancet Oncol 2010; 11: 55–65

• Conclusion:– High RS, LN (+), ER(+) benefit from

addition of CAF to Tamoxifen in free survival (HR, 0.59; log rank P=.033) with the addition of CAF

– Low RS did not benefit from adjuvant chemotherapy, despite positive node.

• The use of Oncotype DX may identify– LN(-), ER (+) EBC with high risk of recurrence. – LN(+), ER (+) EBC with low risk of recurrence may not have

benefit from chemotherapy.

NCCN guideline

• TAILORx trial: – 11,000 patients with ER+, HER2–, node-negative breast cancer.– RS: Arm A: <11, B/C: 11-25 , D:>25– Trial enrollment completed in 2010 and trial results are not yet available.

• RxPONDER trial (SWOG S1007) January 2011– ER+, HER2– breast cancer with 1 to 3 positive nodes (N1)– Enroll 4000 women with an RS of 25 or less, 2000 patients per arm

planned– The primary

• effect of chemotherapy on LN(+) breast cancer who have an RS of 25 or less.– Secondary objectives

• comparison of Oncotype DX and PAM50 risk of relapse (ROR) scores

Prospective Clinical Trials of Oncotype DX:TAILORx and RxPONDER

PAM50 ROR score

PAM50 ROR score• Use RT-qPCT to categorizes tumors into the 4 intrinsic subtypes

– luminal A– luminal B– HER2-enriched– basal-like

• ROR score to estimate the probability of relapse at 5 years.

Parker el al. J Clin Oncol 27:1160-1167

Tamoxifen-treated, early-stage, ER+ breast cancer,

DSS= disease specific survival

Samuel Leung et al. Clin cancer research 2010;16:5222

• NCIC MA12 trial– Predict the benefit of tamoxifen in premenopausal women in the, whereas ER

status alone had limited value.

Dongsheng Tu et al.Clin Cancer Res 2012;18:4465-4472.

IHC status

PAM50

• TransATAC analysis– Good agreement between PAM50 ROR and Oncotype DX– PAM50 ROR score provided more prognostic information

about 10-year distant recurrence than Oncotype DX – More patients assigned to the low-risk category by PAM50.

• half of the patients in the intermediate-risk Oncotype DX group were classified into the low-risk PAM50 luminal A category.

• RxPONDER trial

Dowsett et al 2011 Cancer research

MammaPrint and the MINDACT Prospective Clinical Trial

MammaPrint

• Using DNA microarrays, a 70-gene prognostic signature, MammaPrint, for node-negative breast cancer was developed in 2002. (2002 Nature)– low- or high-risk for distant metastases at 5 years. –MammaPrint outperformed standard clinical and

histologic predictors of patient prognosis. – approved by the FDA in 2007 for node-negative

patients.

• The MINDACT trial (Microarray In Node-negative and 1–3 Node-Positive Disease May Avoid Chemo Therapy)

– Prospective randomized phase III clinical trial–MINDACT had a predefined pilot phase in which

the data and treatment decisions of the first 800 patients were analyzed, and those results were published in 2011. (2011 Eur J Can)

The MINDACT trial

• http://www.lifemath.net/cancer/breastcancer/therapy/

• Chemotherapy: – anthracycline-containing regimen – or docetaxel/capecitabine.

• Endocrine therapy: – a switching strategy of tamoxifen for 2 years, then letrozole for 5 years,

versus – letrozole for 7 years

• Question 1: Should we use gene-predictors to define the need of adjuvant treatment?

• MammaPrint – prognosis in untreated node-negative patients.– 29% discordance in low and high risk groups

between Adjuvant! and MammaPrint• 32% low risk with Adjuvant!

– => high risk with MammaPrint• 68% high risk with Adjuvant!

– => low risk with MammaPrint

– The MINDACT will address this issue

• Question 2: Should we use gene predictors to guide treatment choice, particularly to understand if an ER-positive tumor needs chemotherapy in addition to hormone therapy?

• NCCN suggest– Chemotherapy in case of node positivity– Oncotype DX :negative nodes with T>1 cm

• St. Gallen suggest– favor chemotherapy if a tumor is >5 cm or if 4+ metastatic nodes.

• If a tumor is between 2 and 5 cm, or if only 1-3 nodes positive?– Oncotype DX

• High recurrent score: predict chemotherapy benefit• Low recurrent score: no evidence of benefit.

• Gray zone in intermediate RS– RS: 11- 25, 45% of all subjects– Ongoing TAILORx trial

• Question 3: Can we use genomic predictors to choose the type of chemotherapy?

• A multigene signature predictive of the activity of paclitaxel and 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC), in neoadjuvant setting– Complete pathological response : more powerful

predictor of treatment outcome.– multigene signature

• positive predictive value is modest (52%)• negative predictive value is high (92%)

• We can probably select what not to use, but not what to use

Ayers M el al. J Clin Oncol 2004;22(12):2284

• Question 4: Are genomic predictors ready for routine clinical practice?

• Combining one or more gene-expression classifiers into a single model together with traditional clinico-pathological parameters hat still retain important prognostic information.

Future Developments: Cancer Genome Sequencing

• A revolution in DNA sequencing technology began in 2005.

• 2009–2010 ,Washington University School of medicine.

• Sequenced the patient’s normal DNA, the primary tumor DNA, and the DNA of the metastasis– identified somatic DNA changes.– significant evolution in the cancer can occur during

metastatic spread

• Luminal subtype breast cancers, a statistically significant difference (P=.02) is seen in the number of point mutations – Point mutation– black: copy number– green: interchromosome translocation– blue: intra-chromosome

• Similarly, comparison of the genomes of basal-like, HER2-enriched, luminal A, and luminal B breast cancers, as defined by PAM50, shows that the number of translocations is much higher in basal-like and HER2-enriched cases. (2012 nature)

• The neoadjuvant AI trial, ACOSOG Z1031, were sequenced– TP53

• higher preoperative endocrine prognostic index scores• higher pretreatment and posttreatment proliferation indexes.

– GATA3 • mutations in the transcription factor• associated with response to AI therapy.

– MAP3K1• low pre– and post–AI treatment Ki-67 level (the opposite of p53)• correlated with good-prognosis breast cancer.

• Genome sequencing– may identify the molecular abnormalities – identified poor risk by multigene tests– provide potential new targets for therapy

Thanks for your attention~