2013 SABCS Review

Shou-Ching TangMD, PhD, FACP, FRCP (C)

GRU Cancer Center

Nothing to declare

Disclosure

outline

• Prognostic and predictive biomarkers• Prevention• Early breast cancer• locally advanced breast cancer• Advanced breast cancer• Targeted therapy• Conclusion

Prognostic and predictive biomarkers

Genetic landscape of MBCBachelot et al, #S6-07, SABCS 2013

• Exome sequencing of 100 pairs of MBC and normal breast tissue DNA (Integragen Inc, Hiseq platform)

• Targeted sequencing of 100 genes in 240 MBC biopsies

• PIK3CA 26%, AKT1 4%, PTEN 4%, ERBB 2%, K-Ras 1%, ATM 1%, CDH1 2%, GATA3 2%. PTPN11 1%, PTPRD 1%, ROS1 1%

• Many of them are drugable and involved in metastatic process and drug resistance

Exome sequencing to identify actionable mutations in mTNBC

Blackwell et al, S4-04, SABCS 2013

• 38 pts with mTNBC and matched specimens of germ-line DNA, primary and metastatic tumors

• Whole-exome sequencing by Agilent solution-based system of exon capture with 10 GB of sequencing data

• Striking genetic heterogeneity between primary and metastatic tumors

continues

Exome sequencing to identify actionable mutations in mTNBC

Blackwell et al, S4-04, SABCS 2013

• No single driver mutation that was common to metastatic tumors, indicating diverse genetic pathways contributing to metastasis

• Mutations in APC and mTOR more frequent in metastatic than primary tumors

• Nonsense mutations of ER in primary and metastatic tumors but not in germ-line DNA

• EGFR and HER2 mutations not detected

Gene mutations and protein expression in TNBC vs non-TNBC

O’Shaughnessy et al, #PD4-1, SABCS 2013

• 5500 pts evaluated for mutation (Sanger or Illumina Truseq), protein expression (IHC) and/or amplification/rearrangement (FISH or CISH), 16% with TNBC

• Mutation: TNBC has higher p53 mutation (60% vs 30%), lower PIK3CA (12% vs 31%)

• Amplification: TNBC has higher amplification of EGFR (24% vs 13%), lower HER2, PIK3CA, cMYC and TOP2A

• IHC: TNBC has higher AR (56% vs 15%)

Community-based NGS to guide clinical trial selection

Yardley et al, abst PD4-3, SABCS 2013

• 594 advanced BC profiled• Most frequently altered gene: PIK3CA (24%), followed by

RUNX1 (4%) and FGFR3 (2%)• Infrequent: PIK3R1, MET, KRAS, KIT, FGFR2, HER2, BRAF,

SMO, MYC, DDR2 and AKT1, one pt each• 6% pts enrolled in phas I trials based on NGS (PI3K and

mTOR inhibitor), 29% pts potentially eligible for ongoing trials at SCRI

• PIK3CA mutation accounted for 70% of 35% actionable mutations detected

10

PI3KCA mutation predicts resistance in HER2+/ER+ BC

Loibl et al, #S4-06, SABCS 2013

• Prospectively analyzed 512 pts from Geparsixto and validated in 225 pts from GeparQuinto trials

• PI3KCA mutation found in 19.2% HER2+ tumors, more in HER2+/ER+, 21.5% pCR in pts with and without PI3KCA mutation

22.7 vs 43.6 %, p=0.001with HER2+/ER+ tumors

6.5% vs 30.8%, p=0.005 No difference in HER2+/ER- tumors

42.9% vs 46.1%, p=0.852

11

PIK3CA mutation and/or low PTEN predict resistance to lapatinib and trastuzumab

Contreras, et al, #PD1-2, SABCS 2013

• Neoadjuvant L plus T (no chemo) x 12 wks • 59 pts tested for PTEN (IHC) and 33 for PI3KCA

mutation (36% by NGS)• pCR: overall 16%

high vs low PTEN 32% vs 9% p=0.04 PIK3CA mutation: 0% p=0.06 low PTEN and PIK3CA mutation vs normal:

0% vs 36% p=0.01

12

Prognostic value of tumor infiltrating lymphocytes (TIL’s)

• % of lymphocyte infiltration in tumor stroma reflects host immune reaction

• The presence of TIL’s was correlated with benefit from:– trastuzumab in HER2+ EBC in 156 pts from the

neoadjuvant GeparQuattro trial (Loi et al, #S1-05, SABCS 2013)

– the addition of carbo to neoadjuvant therapy in TN and HER2+ EBC in Geparsixto trial (Dunkert, et al, #S1-06)

– adjuvant therapy in ECOG 2197 and 1199 in TNBC (Adams et al, #S1-07, SABCS 2013)

SWOG S0500 CTC’s in guiding CT in MBCSmerage et al, #S5-07, SABCS 2013

(CTC found in 75% MBC, half >5CTC/7.5 ml whole blood)

Primary end point: OS

SWOG S0500 CTC’s in guiding CT in MBC

Smerage et al, #S5-07, SABCS 2013

• Conclusion:– CTC prognostic in MBC at baseline and after first

chemo– Changing chemo based on CTC after first chemo

does not affect OS or PFS

prevention

IBIS-II Chemo-prevention in high risk postmenopausal women

Cuzick et al, #S3-01, SABCS 2013

• Randomized phase III UK trial• 3864 women with high risks of BC, median

f/u 5.03 yrs• Primary end point: incidence of BC, including

DCIS• Anastrozole vs placebo for 5 years

IBIS-II: Chemo-prevention in high risk postmenopausal women

Cuzick et al, #S3-01, SABCS 2013

• 5-yr BC incidence: 53% reduction, p<0.0001• Significant reduction in all invasive BC (50%), ER+ BC

(58%) and DCIS (70%)• Significant reduction of cancer at other sites (RR=0.58)• Deaths from BC and other causes similar in both arms• Musculoskeletal and vosomotor events higher and

bone # non-significantly higher in anastrozole arm• In support of other chemoprevention trials: TAM

(NSABP P-1), raloxifen (STAR)and exemestane (MAP3)

Early breast cancer

Hormone and physical exercise (HOPE) in EBC

Irwin et al, #S3-03, SABCS 2013

• Randomized phase III multicenter US trial• 121 pts on adjuvant AI for > 6 m and with >3/10 worst

joint pain on Brief Pain Inventory-Short form (BPI) • 150 min/wk mod-intense aerobic exercise and twice-

wkly supervised resistance exercise or usual care• Primary end point: change in BPI worse joint pain

score between 0-12 momths• reduction of BPI score (20% vs 3% , p=0.017), joint

pain intensity (p=0.025), body wt (p=0.0057) and increase in cardiopulmonary fitness (p=0.024)

• Impact on adherence to AI’s and survival?

36 randomized trials, 22,982 ptsPrimary end point: time to recurrence, to first distance recurrence and breast cancer mortality

Bisphosphonates and survival in EBC: meta-analysis

Coleman et al, #S4-07, SABCS 2013

Bisphosphonates and survival in EBC: meta-analysis

Coleman et al, #S4-07, SABCS 2013

RR 10-yr gain % 2p value

All ptsBC mortality 0.91 1.7 0.04distance recurrence 0.92 1.3 0.05

Post-menopausal ptsBC mortality 0.83 3.1 0.004distance recurrence 0.83 3.3 0.0007

Bisphosphonates and survival in EBC: meta-analysis

Coleman et al, #S4-07, SABCS 2013

• Reduction in bone relapse in postmenopausal pts similar regardless of type of BP tx, duration and schedule or concomitant chemotherapy

• Adjuvant BP improves survival in postmenopausal pts with EBC

• No benefit in premenpausal pts in bone or other recurrences

• Currently indicated for prevention or treatment of bone loss

Phase II study of TH in HER2+ and node- EBC

Tolaney, S et al, #S1-04, SABCS 2013

• 410 pts, HER2+ EBC• T1mi 3%; T1a 27%, T1b 20%, T1C 41%, T2<3 cm 9%• Wkly paclitaxel x12 with trastusumab for one year• Null hypothesis: 3-year failure rate of 9.2% (failure)• Alternative hypothesis: 3-year failure rate of 5%

(success)• Due to limited number of events, DMSB approved data

release with 1316 PYFU and median f/u of 3.2 years

TH in node-/HER2+ EBC

• TH is highly effective and well tolerated• Can be considered an option in majority of stage

1 HER2+ EBC• Single arm study, 67% HR+ tumor, limited follow

up of 3.6 years• Superior survival data suggest not all pts with

stage 1 HER2+ EBC require trastuzumab-based chemotherapy, esp those with T1aN0 tumor

• Addition of another biological agent to TH backbone is unlikely to have substantial benefit in this pt population (TDM-1 vs TH ongoing)

Primary results of BETH trial in HER2+, node+ or node- high risk EBC

Slamon D et al, #S1-03, SABCS 2013

Docetaxel x 6Carboplatin x 6Trastuzumab x 1 y

Docetaxel x 3Trastuzumab x 1 y

5-FU x 3Epirubicin x 3Cylophos x 3

or

Bevacizumab 15mg q3 wk x 1 y

Observation

BETH Trial3509 pts, phase IIIMedian f/u 3 yearsInvasive disease-free survival (IDFS)

92%

8%

BETH primary result

• Addition of one year bevacizumab to chemotherapy did not prolong invasive disease-free survival (IDFS)

• TCH is an effective adjuvant regimen for pts with HER2+ EBC, including node+ tumors

• No new or unexpected safely signals• No added benefit of bev in MBC, LABC and EBC in

unselected pts, biomarker studies urgently needed (ongoing repeat of ECOG trial with biomarkers included)

GIM-2 EC or FEC with dd P or not in node+ EBC

Cognetti et al, # S5-06, SABCS 2013• Italian multicenter randomized phase III 2x2

design• 2019 pts, node+, < 70 yo, median f/u 7 yrs• EC x4 or FEC x4 then P q 2 (with G) or 3 wks x4• Primary end point: DFS• DD CT improved DFS and OS : HR 0.78 (p=0.007)

and 0.68 (p=0.002) respectively• Benefit of DD CT independent of HR status• Addition of F to EC did not improve outcome

PRIME II: Adjuvant RT in pts > 65 yoKunkler et al, #S2-01, 2013 SABCS

• Multicenter UK trial, 1326 pts, median f/u 5 yrs• >65 yo, T 1-2 (up to 3 cm), N0/M0, HR+, margin > 1mm, could

be grade 3 or LVI but not both, required adjuvant hormonal therapy

• Primary end point: ipsilateral breast tumor recurrenceno RT (%) RT (%) p

–IBTR 4.1 1.3 0.01–OS 93.8 94.2 0.24–Regional relapse 1.4 0.5–Contralateral relapse 0.9 1.9–Distance relapse 1.0 0.3

• Results similar to CALGB, ECOG and RTOG trial (pASCO 2010)• Omission of adjuvant RT safe in selected older pts

10-yr survival update of NSABP B-32Julian et al, #S2-05, SABCS 2013

• Randomized phase III of SLND plus ALND or ALND

• 5611 pts• Still no difference in OS, DFS and loco-regional

relapse (HR 1.09, p=0.35; HR 1.02, p=0.72; HR 0.96, p=0.77 respectively)

• No difference in OS and DFS in pts with occult mets detected by IHC with or without ALND

• IHC has no prognostic role in EBC

Locally advanced breast cancer

Neo ALTTO Survival updatePiccar-Gebhart, M et al, #S1-01, SABCS 2013

Stratification:• T ≤ 5 cm vs. T > 5 cm•ER or PgR + vs. ER & PgR –• N 0-1 vs. N ≥ 2•Conservative surgery or not

Invasive operableHER2+ BCT > 2 cm (inflammatory BC excluded)LVEF 50%N=450

34 weeks

52 weeks of anti-HER2 therapy

lapatinib

trastuzumab

lapatinibtrastuzumab

SURGERY

RANDOMIZE

lapatinib

trastuzumab

lapatinibtrastuzumab

paclitaxel

paclitaxel

paclitaxel

+ 12 wks6 wksMedian f/u 3.77 years

NeoALTTO Efficacy – pCR and tpCR

L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumabpCR pathologic complete response HR: hormone receptors

Baselga J et al. SABCS 2010; abstract S3-3

NeoALTTO survival update• First study to show that pts with pCR had

significantly better EFS and OS with HER2+ tumors

• Study was powered to detect difference in pCR, but underpowered to detect moderate difference in survival

• Dual HER2 blockade is superior • HER2+/HR- and HER2+/HR+ subgroups are

different diseases

TRIO-US B07 final analysisHurvitz S et al, #S1-02, SABCS 2013

• Randomized phase II of neoadjuvant H or L or both in stage 1-3, HER2+ EBC

• 106 pts in 13 US centers, primary end point, pCR• Run-in cycle of H or L or both followed by 6 cycles

of TCH (A) vs TCL (B) or TCHL (C)• Overal pCR: 42% (A 43%, B 25% and C 52%,

p=0.069)• Pair-wise comparison: pCR in B significantly lower

than C (p=0.021), not different between A and B (p=0.14) and A and C (p=0.45)

CALGB 40603 (Alliance) neoadjuvant carbo +/- Bev in TNBC

Sikov et al, #S5-01, SABCS 2013

2x2 randomized phase II in locally advanced TNBC in 545 pts

CALGB 40603 (Alliance) neoadjuvant carbo +/- Bev in TNBC

Sikov et al, #S5-01, SABCS 2013

• pCR (%, breast and axilla):no Cb Cb Bev effect

No Bev 28.2 42.4 10.5Bev 42.6 50.0 p=0.031Cb benefit 10.3 p=0.033

• Addition of Cb or Bev to NAC significantly increases pCR in TNBC, and the increases are additive

• Several studies now support the addition of Cb to standard CT in LABC (CALGB 40604, GeparSixto and I-Spy 2), adjuvant trials ongoing

Paclitaxel + Trastuzumab* +

New Agent A

Paclitaxel + New Agent C

Patient is on Study

Paclitaxel+ Trastuzumab

Paclitaxel + Trastuzumab* +

New Agent B

Paclitaxel

Paclitaxel + New Agent E

AC

ACHER 2 (+)

HER 2(–)

Randomize

Randomize

Surgery

Surgery

Learn and adapt from each patient as we go

along

Paclitaxel + New Agent F

Paclitaxel + Trastuzumab* +

New Agent C

Paclitaxel + New Agent DPaclitaxel +

New Agent GH

Paclitaxel + Trastuzumab* +

New Agent F

*Investigational agent may be used in place

MRI

ResidualDisease(Pathology)

Key

I-SPY 2 TRIAL:I-SPY 2 TRIAL:

Learn, Drop, Graduate, and Replace Agents Over Time

I-SPY 2: the first graduateRugo et al, #S5-02, SABCS, 2013

• Primary end point: pCR• Graduate regimens have >85% Bayesian predictive

probability of success in a 300-pts biomarker-linked neoadjuvant phase III trial

• Veliparib+carbo met the 85% predictive probability criterion in HR-/HER2- and all HER2- pts% pCR p V+Cb better p of successful phase III

All HER2- 35 vs 20 97% 71% HR+/HER2- 14 vs 15 44% 16% TNBC 52 vs 24 99% 92%

• V/Cb graduated with a TNBC signature and recommended for future trial

• Biomarker study? (lesson from iniparib)

NATAN, post-neoadjuvant zoledronate trialvon Minckwitz et al, #S5-05, SABCS 2013

• Randomized phase III trial in 693 pts with residual tumor after at least 4 cycles of NAC with taxanes and anthracyclines, median f/u 48 m

• Z q4wks x6m, q3mx2yrs and q6mx2.5 yrs for 5 yrs vs no

• Primary end point: EFS at 5 years• DFS: HR 0.96 p=0.7885• OS: HR p=0.4082• Decreased BC mortality in post-menopausal pts:

RR 0.83 (SE 0.06)

Metastatic breast cancer

Resection of primary BC and ALN in MBCBadwe et al, #S2-02, SABCS 2013

• Randomized phase III trial, local regional treatment (LRT) or not, 350 pts, median f/u 17 months,

• Primary end point: OS • Median survival (M): 18.8 vs 20.5, HR=1.07, p=0.60• Overall survival at 2-yr (%): 40.8 vs 43.3• No difference in OS after adjusting age, ER, HER2, site

and # of metastasis in Cox regression model (p=1.00)• LRT should be reserved for palliative reasons

Resection of primary BC in de novo stage IV MBC

Soran et al, #S2-03, SABCS 2013• Randomized Turkish trial of LRT vs not, 278 pts,

median f/u 21.2 +/- 14.5 m• Type of LRT and systemic therapy at the

discretions of SO and MO• Primary end point: OS• OS at 5 m (%): 35 vs 31, p=0.24• OS longer in pts with bone only, HR+, age <50 yr

but shorter in TNBC • Ongoing US cooperative trial (E2108)

ROSE/TRIO-12 trial of ramucirumab in MBC

Mackey et al, #S5-04, SABCS 2013

• Randomized multicenter phase III trial of ramucirumab (anti-VEGFR2) or placebo in first line HER2- MBC, with biomarker study

• 1144 pts, 1:2 randomization• Primary end point: PFS• Median f/u 16.3 m

Targeted therapy

Cross-talks among signal transduction pathways

Dual function of YAP-1 in canerWang and Tang, Can and Met Rev, 2013

Letrozole plus dasatinib improves PFS in MBC

Paul et al, #S3-07, SABCS 2013• Randomized phase II multicenter USO trial• HR+, HER2- MBC first line, 116 evaluable pts• Adjuvant AI allowed if completed > 1yr before entry• Letrozole +/- dasatinib (Src TKI), cross over allowed• Primary end point: CBR (PR/CR/SD>6m)

DL LCBR (%) 71 66PFS (M) 22 11 p=0.05

• Toxicities: fatigue (38%), nausea (38%), anemia (25%), rash (23%), pleural effusion (16%) and edema (13%)

• 27% pts required dose reduction for dasatinib• Other promising drugs: everolimus, palbociclib, HDACI,PI3KI

New Drugs to Overcome Resistance in Hormonal Therapy

Afinitor Product W Product X Product YMechanism of Action

• mTOR inhibitor • CDK4/6 kinase inhibitor

• HDAC inhibitor • P13K inhibitor

Comparator • Exemestane • Letrozole • Exemestane • Fulvestrant

Median PFS • Afinitor + Exemestane -7.8 months vs. Exemestane alone -3.2 months (HR = 0.45)

• Product W + Letrozole -26.1 months vs. Letrozole alone -7.5 months (HR = 0.37)

• Product X + Exemestane -7.1 months vs. Exemestane alone -4.1 months (HR = 0.58)

N/A

Median OS • OS results are not mature

N/A Product X + Exemestane -29.3 months vs. Exemestane alone -22 months (HR = 0.75)

N/A

Ziaudinn and TangReview paper in preparation

Summary

• Genetic alteration is common in primary and metastatic tumors and in tumors undergoing treatment

• Identification of biomarkers and drugable mutations by genome sequencing will not only unravel mechanismS of drug resistance but help to offer pts tailored targeted therapy

• TIL’s are associated with favorable response to breast cancer chemotherapy

Summary-2

• Biosphophonates reduce tumor relapse in postmenopausal women with EBC, current approval is for their use in bone loss

• Pts with stage I HER2+ tumors may be offered TH chemotherapy

• Anti-angiogenesis (bev and ramucirumab) is unlikely effective in unselected pts with BC, biomarker studies are urgently needed

Summary-3• Veliparib and/or carboplatin added to taxane

backbone increase pCR in TNBC• Surgical management of primary tumor in pts

with MBC does not improve survival and should only be considered for symptom control and in clinical trials

• Dasatinib increases the efficacy of letrozole in MBC. Blocking cross talks of ER pathways will help to overcome drug resistance

Acknowledgement

• Industry supporters: Amgen, Genomic Health and Merck

• GRU support team: Susan Everitt, Lisa Middleton and Caroline English

• GRU Cancer Center Leadership and educational grant

Thank you