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2013 SABCS Review Shou-Ching Tang MD, PhD, FACP, FRCP (C) GRU Cancer Center.

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Presentation on theme: "2013 SABCS Review Shou-Ching Tang MD, PhD, FACP, FRCP (C) GRU Cancer Center."— Presentation transcript:

1 2013 SABCS Review Shou-Ching Tang MD, PhD, FACP, FRCP (C) GRU Cancer Center

2 Nothing to declare Disclosure

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

4 Prognostic and predictive biomarkers

5 Genetic landscape of MBC Bachelot 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

6 Exome sequencing to identify actionable mutations in mTNBC Blackwell et al, S4-04, SABCS 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

7 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

8 Gene mutations and protein expression in TNBC vs non-TNBC O’Shaughnessy et al, #PD4-1, SABCS 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%)

9 Heterogeneity between primary and met BC prior to Tx Bidard et al, #S6-06, SABCS 2013 High-depth whole exome sequencing and SNP6 copy number profiling of primary and met biopsies from 7 pts with de novo MBC prior to systemic therapy Significant genomic differences between primary and met tumors Median 105 of single nucleotide variants (SNVs) and 54 insertions/deletions (indels) identified, of which 36 and 11 were shared between the primary and secondary tumors 50% driver SNV’s and 70% pathogenic indels were restricted to either primary or met tumors, including the epithelial-to-mesenchymal transition (EMT)-related genes TGFB1, SMAD4 and TCF7L2

10 Community-based NGS to guide clinical trial selection Yardley et al, abst PD4-3, SABCS 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

11 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=0.001 with HER2+/ER+ tumors 6.5% vs 30.8%, p=0.005 No difference in HER2+/ER- tumors 42.9% vs 46.1%, p=

12 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=

13 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)

14 SWOG S0500 CTC’s in guiding CT in MBC Smerage et al, #S5-07, SABCS 2013 (CTC found in 75% MBC, half >5CTC/7.5 ml whole blood) Primary end point: OS

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19 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

20 PAM50 to predict late relapse in EBC Sestak et al, #S6-04, SABCS pts from ABCSG-8 and transATAC trials who did not relapse in 0-5 yrs Clinical treatment score (CTS, from transATAC) is the strongest prognostic score for late relapse PAM50 risk of recurrence (ROR) score adds significant prognostic value for late relapse Risk of distant relapse at 10 yrs for low risk group is 5.7%, intermediate risk 14.6% and high risk 29.3% Pts with luminal A subtype had a 70% lower risk of distant relapse than luminal B (HR 0.03, p<0.0001)

21 prevention

22 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

23 IBIS-II: Chemo-prevention in high risk postmenopausal women Cuzick et al, #S3-01, SABCS yr BC incidence: 53% reduction, p< 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)

24 Early breast cancer

25 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?

26 36 randomized trials, 22,982 pts Primary 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

27 RR10-yr gain %2p value All pts BC mortality distance recurrence Post-menopausal pts BC mortality distance recurrence

28 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

29 Phase II study of TH in HER2+ and node- EBC Tolaney, S et al, #S1-04, SABCS 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

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31 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)

32 Primary results of BETH trial in HER2+, node+ or node- high risk EBC Slamon D et al, #S1-03, SABCS 2013 Docetaxel x 6 Carboplatin x 6 Trastuzumab x 1 y Docetaxel x 3 Trastuzumab x 1 y 5-FU x 3 Epirubicin x 3 Cylophos x 3 or Bevacizumab 15mg q3 wk x 1 y Observation BETH Trial 3509 pts, phase III Median f/u 3 years Invasive disease-free survival (IDFS) 92% 8%

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37 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)

38 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

39 PRIME II: Adjuvant RT in pts > 65 yo Kunkler 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 recurrence no RT (%)RT (%) p – IBTR – OS – Regional relapse – Contralateral relapse – Distance relapse Results similar to CALGB, ECOG and RTOG trial (pASCO 2010) Omission of adjuvant RT safe in selected older pts

40 10-yr survival update of NSABP B-32 Julian 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

41 Locally advanced breast cancer

42 Neo ALTTO Survival update Piccar-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 operable HER2+ BC T > 2 cm (inflammatory BC excluded) LVEF  50% N= weeks 52 weeks of anti-HER2 therapy lapatinib trastuzumab lapatinib trastuzumab SURGERYSURGERY RANDOMIZERANDOMIZE lapatinib trastuzumab lapatinib trastuzumab paclitaxel + 12 wks 6 wks Median f/u 3.77 years

43 NeoALTTO Efficacy – pCR and tpCR L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab pCR pathologic complete response HR: hormone receptors Baselga J et al. SABCS 2010; abstract S3-3

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48 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

49 TRIO-US B07 final analysis Hurvitz 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)

50 CALGB (Alliance) neoadjuvant carbo +/- Bev in TNBC Sikov et al, #S5-01, SABCS x2 randomized phase II in locally advanced TNBC in 545 pts

51 CALGB (Alliance) neoadjuvant carbo +/- Bev in TNBC Sikov et al, #S5-01, SABCS 2013 pCR (%, breast and axilla): no CbCbBev effect No Bev Bev p=0.031 Cb benefit10.3 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

52 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 HER 2 (+) HER 2 (–) Randomize Surgery Learn and adapt from each patient as we go along Paclitaxel + New Agent F Paclitaxel + Trastuzumab* + New Agent C Paclitaxel + New Agent D Paclitaxel + New Agent GH Paclitaxel + Trastuzumab* + New Agent F *Investigational agent may be used in place MRI Residual Disease (Pathology) Key I-SPY 2 TRIAL: Learn, Drop, Graduate, and Replace Agents Over Time

53 I-SPY 2: the first graduate Rugo 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)

54 NATAN, post-neoadjuvant zoledronate trial von 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= OS: HR p= Decreased BC mortality in post-menopausal pts: RR 0.83 (SE 0.06)

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59 Metastatic breast cancer

60 Resection of primary BC and ALN in MBC Badwe 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

61 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 / 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)

62 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

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67 Targeted therapy

68 Cross-talks among signal transduction pathways

69 Dual function of YAP-1 in caner Wang and Tang, Can and Met Rev, 2013

70 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) DLL CBR (%)7166 PFS (M)2211p=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

71 New Drugs to Overcome Resistance in Hormonal Therapy AfinitorProduct WProduct XProduct Y Mechanism 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 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/AProduct X + Exemestane months vs. Exemestane alone - 22 months (HR = 0.75) N/A Ziaudinn and Tang Review paper in preparation

72 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

73 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

74 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

75 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

76 Thank you


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