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2013 SABCS Review

2013 SABCS Review. Shou-Ching Tang MD, PhD, FACP, FRCP (C) GRU Cancer Center. Disclosure. Nothing to declare. outline. Prognostic and predictive biomarkers Prevention Early breast cancer locally advanced breast cancer Advanced breast cancer Targeted therapy Conclusion.

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2013 SABCS Review

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

  2. Disclosure Nothing to declare

  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 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

  6. Exome sequencing to identify actionable mutations in mTNBCBlackwell 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

  7. Exome sequencing to identify actionable mutations in mTNBCBlackwell 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-TNBCO’Shaughnessy et al, #PD4-1, SABCS 2013 • 5500 pts evaluated for mutation (Sanger or IlluminaTruseq), 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. Community-based NGS to guide clinical trial selectionYardley 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+ BCLoibl 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=0.852

  11. PIK3CA mutation and/or low PTEN predict resistance to lapatinib and trastuzumabContreras, 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)

  13. 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

  14. SWOG S0500 CTC’s in guiding CT in MBCSmerage 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

  15. prevention

  16. IBIS-II Chemo-prevention in high risk postmenopausal womenCuzick 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

  17. IBIS-II: Chemo-prevention in high risk postmenopausal womenCuzick 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)

  18. Early breast cancer

  19. Hormone and physical exercise (HOPE) in EBCIrwin 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?

  20. Bisphosphonates and survival in EBC: meta-analysisColeman et al, #S4-07, SABCS 2013 36 randomized trials, 22,982 pts Primary end point: time to recurrence, to first distance recurrence and breast cancer mortality

  21. Bisphosphonates and survival in EBC: meta-analysisColeman et al, #S4-07, SABCS 2013 RR 10-yr gain % 2p value All pts BC mortality 0.91 1.7 0.04 distance recurrence 0.92 1.3 0.05 Post-menopausal pts BC mortality 0.83 3.1 0.004 distance recurrence 0.83 3.3 0.0007

  22. Bisphosphonates and survival in EBC: meta-analysisColeman 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 premenpausalpts in bone or other recurrences • Currently indicated for prevention or treatment of bone loss

  23. Phase II study of TH in HER2+ and node- EBCTolaney, 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

  24. 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)

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

  26. 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)

  27. GIM-2 EC or FEC with dd P or not in node+ EBCCognetti 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

  28. 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 recurrence no 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

  29. 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

  30. Locally advanced breast cancer

  31. Neo ALTTO Survival updatePiccar-Gebhart, M et al, #S1-01, SABCS 2013 Invasive operable HER2+ BC T > 2 cm (inflammatory BC excluded) LVEF  50% N=450 lapatinib lapatinib paclitaxel R A N D O M I Z E S U R GE R Y F E C X 3 trastuzumab trastuzumab paclitaxel • Stratification: • T ≤ 5 cm vs. T > 5 cm • ER or PgR + vs. • ER & PgR – • N 0-1 vs. N ≥ 2 • Conservative surgery • or not lapatinib lapatinib trastuzumab trastuzumab paclitaxel 6 wks + 12 wks 34 weeks Median f/u 3.77 years 52 weeks of anti-HER2 therapy

  32. 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

  33. 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

  34. 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) • OveralpCR: 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)

  35. CALGB 40603 (Alliance) neoadjuvant carbo +/- Bev in TNBCSikov et al, #S5-01, SABCS 2013 2x2 randomized phase II in locally advanced TNBC in 545 pts

  36. CALGB 40603 (Alliance) neoadjuvantcarbo +/- Bev in TNBCSikov et al, #S5-01, SABCS 2013 • pCR (%, breast and axilla): no CbCb Bev effect No Bev 28.2 42.4 10.5 Bev 42.6 50.0 p=0.031 Cb 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

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

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